Somatostatin receptor antagonist compounds and methods of using the same

ABSTRACT

The present invention is directed to somatostatin receptor antagonist compounds having the structure of Formula I:compositions comprising the same, and methods of using such compounds and compositions. The compounds may be useful in the prevention or treatment of hypoglycemia.

CROSS REFERENCE TO RELATED APPLICATION

This application is a continuation application of U.S. patentapplication Ser. No. 16/076,826, filed on Aug. 9, 2018, which is anational phase application under 35 U.S.C. § 371 of InternationalApplication No. PCT/CA2017/050156 filed Feb. 9, 2017, which claims thebenefit of U.S. Provisional Patent Application Ser. No. 62/293,216,filed Feb. 9, 2016, the entire contents of which are hereby incorporatedby reference for all purposes as if fully set forth herein.

TECHNICAL FIELD

This invention relates to compounds that are somatostatin receptorantagonists. More particularly, this invention relates to cyclicpeptides and more particularly to cyclic octapeptides that aresomatostatin receptor antagonists.

BACKGROUND OF THE INVENTION

Somatostatin receptors are ubiquitously expressed in most tissues of thebody. Five different subtypes of somatostatin receptors have beendiscovered. The localization of particular receptor subtypes ondifferent tissues allows for specific receptor antagonists to exertspecific inhibitory effects.

In a series of structure activity relationship (SAR) studies of the 14amino acid version of somatostatin (SST-14) and its analogs (Freidinger,R. M., et al., International journal of peptide and protein research23(2):142-50, 1984; Pattaroni, C., et al., International journal ofpeptide and protein research 36(5):401-17, 1990; Veber, D. F., et al.,Life sciences 34(14):1371-8, 1984), the four amino acid sequencePhe⁷-Trp⁸-Lys⁹-Thr¹⁰ (residues 7-10 of SST-14) was reported to beimportant for binding and activity of somatostatin. While Trp⁸-Lys⁹appears essential, slight modifications in positions 7 and 10 werereportedly possible (Patel, Y. C., Frontiers in neuroendocrinology20(3):157-98, 1999). Furthermore, cyclization (via the Cys-Cys pair atpositions 3 and 14) apparently stabilizes the conformation of theseresidues, mimicking a β-turn, in a manner favorable for binding to SSTreceptors (Veber, D. F., et al., Life sciences 34(14):1371-8, 1984;Veber, D. F., et al., Nature 280(5722):512-4, 1979). Following thesefindings, several agonist analogs of somatostatin have been producedover the past several decades and several agonists have been usedclinically to treat glandular tumors. Octreotide (Novartis) andlanreotide (Ipsen) are indicated for the treatment of acromegaly(somatotrophic adenoma) and thyrotrophic adenoma and in the managementof certain neuroendocrine tumors in the pancreas (e.g., carcinoidtumors). A newer agonist, pasireotide (Novartis), is also usedclinically for the treatment of Cushing's Disease (corticotropicadenoma) (Boscaro, M., et al., The Journal of clinical endocrinology andmetabolism 94(1):115-22, 2009), (see www.signifor.com). Bass et al. (atAmerican Cyanamid) (Bass, R. T., et al., Molecular pharmacology50(4):709-15, 1996) reported that substitution of D-cysteine at theposition equivalent to residue 3 of SST-14 gave analogs with antagonistactivity. Since then, antagonists that bind to the various SST receptorsubtypes with different affinities have been developed.

One approach to reducing hypoglycemia is to inhibit somatostatinreceptors related to counterregulatory hormone release which are foundin the pancreas, adrenal gland, and hypothalamus of the brain.Somatostatin receptor type 2 (SSTR2) are found in these tissues. Withinthe pancreas, SSTR2 are found nearly exclusively on glucagon-secretingα-cells in rodents (Rossowski, W. and Coy, D., Biochemical andBiophysical Research Communications 205:341-346, 1994; Strowski, M., etal., Endocrinology 141:111-117, 2000). In humans as well, somatostatinexerts its inhibitory effect on glucagon secretion via SSTR2 found onα-cells (Kumar, U., et al., Diabetes 48:77-85, 1999; Reubi, J., et al.,J. Clin. Endocrinol. Metab. 83:3746-3749, 1998), while the receptor isalso expressed in the 13 cells (Reubi, J., et al., J. Clin. Endocrinol.Metab. 83:3746-3749, 1998), where it is involved in regulating insulinsecretion. In the adrenal gland, SSTR2 have been widely identified inthe adrenal medulla of animals and humans (Kimura, N., et al., EndocrineJournal 48:95-102, 2001; Maurer, R. and Reubi, J., Molecular andCellular Endocrinology 45:81-90, 1986). It has been shown thatsomatostatin inhibits acetylcholine-stimulated release of epinephrinefrom the adrenal medulla (Role, L., et al., Neuroscience 6:1813-1821,1981; Mizobe, F., et al., Brain Research 178:555-566, 1979), and this isthe mechanism whereby epinephrine is released during hypoglycemia (HavelP. and Taborsky, G. J., Stress-induced activation of the neuroendocrinesystem and its effects on carbohydrate metabolism. In Ellenberg andRifkin's Diabetes Mellitus. Porte Jr D, Sherwin R, Baron A, Eds. NewYork, McGraw-Hill, 2003, p. 127-149). SSTR2 are also found in thehypothalamus of the brain (Fehlmann D., et al., Journal of Physiology(Paris) 94:265-281, 2000; Lanneau C., et al., European Journal ofNeuroscience 10:204-212, 1998) where somatostatin also has an inhibitoryeffect on hormones involved in hypoglycemic counterregulation.

The approach of using SSTR2 antagonism to prevent hypoglycemia has beendemonstrated in the STZ rat model, in which the glucagon response tohypoglycemia, which is absent in diabetic rats can be restored byadministration of a SSTR2 antagonist (Yue J. T., et al., Diabetes61(1):197-207, 2012). In this experiment, not only was the glucagonresponse restored, but the corticosterone response which was alsodeficient in diabetic rats was also improved in hypoglycemia aftertreatment with a SSTR2 antagonist. Furthermore, restoration of thecounterregulatory responses corresponds to prevention or reduction inthe severity of hypoglycemia in similar rats given an insulin dose toinduce hypoglycemia (Yue J. T., et al., Diabetes 62(7):2215-2222, 2013).

Somatostatin levels in the pancreas in diabetic animals are elevated(Rastogi, K., et al., Endocrinology 126:1096-1104, 1990; Rastogi, K., etal., Canadian Journal of Physiology and Pharmacology 71:512-517, 1993)as well as in diabetic humans (Orci, L., et al., Proceedings of theNational Academy of Sciences U.S.A 73:1338-1342, 1976). Instreptozotocin (STZ)-diabetic rats, there is: (i) hyperplasia andhypertrophy of somatostatin-containing δ-cells in the pancreas (Orci,L., et al., Proceedings of the National Academy of Sciences U.S.A73:1338-1342, 1976); (ii) increased expression of pancreaticprosomatostatin mRNA (Brubaker, P., et al., Endocrinology 124:3003-3009,1989; Shi, Z., et al., Endocrinology 137:3193-3199, 1996); (iii)increased pancreatic somatostatin (Inouye, K., et al., American Journalof Physiology Endocrinology and Metabolism 282:E1369-E1379, 2002); and(iv) distribution of somatostatin-secreting δ-cells in the centralportions of islets cells (Rossowski, W. and Coy, D., Biochemical andBiophysical Research Communications 205:341-346, 1994). It has beenreported that excessive somatostatin may inhibit glucagon release duringhypoglycemia (Rastogi, K., et al., Endocrinology 126:1096-1104, 1990).Furthermore, it is well documented that somatostatin inhibits stimulatedsecretion of pancreatic glucagon. In STZ-diabetic rats, the expressionof the gene for pro-glucagon and pro-somatostatin are both markedlyincreased (Inouye, K., et al., American Journal of PhysiologyEndocrinology and Metabolism 282:E1369-E1379, 2002). This increasedconcentration of somatostatin is observed in diabetic rats, both duringeuglycemia (i.e. normal blood glucose concentrations) and hypoglycemia(Shi, Z., et al., Endocrinology 137:3193-3199, 1996). Concentration ofsomatostatin in plasma is also increased during euglycemia andhypoglycemia in diabetic rats (Shi, Z., et al., Endocrinology137:3193-3199, 1996). However, despite increased gene expression ofproglucagon, plasma concentrations of glucagon are not increased duringhypoglycemia in diabetic rats, presumably in part due to the markedelevation of somatostatin levels.

In isolated islets and in perifused isolated islets, the somatostatinreceptor type 2 (SSTR2)-selective antagonist, DC-41-33, also known asPRL-2903, dose-dependently increases glucagon secretion to an argininestimulus, and subsequently adding somatostatin dose-dependently reversesthe actions of the SSTR2 antagonist (Cejvan, K., et al., Diabetes 51Suppl 3:S381-S384, 2002; Cejvan, K., et al., Diabetes 52:1176-1181,2003).

In isolated, perfused pancreas of non-diabetic rats, this antagonistenhances glucagon secretion without affecting insulin secretion (Cejvan,K., et al., Diabetes 52:1176-1181, 2003). Similar findings have beendemonstrated in rat and human pancreatic tissue slices, prefused inhypoglycemic condition with and without SSTR2 antagonist (Karimian N.,et al., Diabetes 62(8):2968-2977, 2013). It is also able to reverse theinhibitory effect of glucose-dependent insulinotropic polypeptides, GIPand GIP-(1-30)NH₂, and glucagon-like polypeptide, GLP-1(7-36)NH₂, onpentagastrin-stimulated gastric acid secretion in non-diabetic rats(Rossowski, W., et al., British Journal of Pharmacology 125:1081-1087,1998). Somatostatin receptor antagonists are described in U.S. Pat. No.4,508,711 (April 1985, Coy et al.) and in U.S. Pat. No. 5,846,934(December 1998, Bass et al.) (Hocart, S. J., et al., Journal ofmedicinal chemistry 42(11):1863-71, 1999; Rajeswaran, W. G., et al.,Journal of medicinal chemistry 44(8):1305-11, 2001).

The primary pharmacological treatments for hypoglycemia on the markettoday are based on various IV glucose or dextrose formulations and, assuch, are considered reactionary treatments rather than true managementstrategies. There are a number of glucagon products on the market (e.g.,GlucaGen®, Novo Nordisk), however this too is a rescue approach and istypically administered IV or SC in emergencies because the patient isunconscious. Importantly, glucagon must also be carefully dosed to avoidoverstimulating glucose production (unlike a normalized endogenousglucagon response). These therapies are not directed to reducing theincidence of hypoglycemia, and as rescue therapies for severehypoglycemia, they would not be expected to reduce the apprehensionpatients feel about the likelihood of experiencing a hypoglycemic event.Preventive therapies are required to reduce or eliminate thiscomplication, and to enable insulin-dependent diabetic patients to moreaggressively manage their blood glucose levels, resulting in overallimproved long-term health outcomes. There is thus a real and strongdemand for the development of a long-term therapeutic approach for theprevention of hypoglycemia.

SUMMARY OF THE INVENTION

This invention is based, in part, on novel cyclic peptides that exhibitsomatostatin receptor (SSTR) antagonist activity. Cyclic peptides of thepresent invention are often selective for a particular SSTR, such asSSTR 2. This invention is also based, in part, on novel amino acids thatcan be used in cyclic peptides of the present invention.

In illustrative embodiments of the present invention, there is provideda compound having the structure of Formula I:

or a salt thereof, wherein:R^(C) is OH or NHR¹⁶, wherein R¹⁶ is H or C₁₋₆ alkyl optionallysubstituted with one or more substituents;R^(N) is selected from the group consisting of:

-   -   (i) H;    -   (ii) C₁₋₆alkyl;    -   (iii) —C(O)R¹⁷, wherein R¹⁷ is selected from the group        consisting of C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-membered        heteroaryl, wherein the C₁₋₆alkyl is optionally substituted with        one or more substituents, and wherein the C₆₋₁₀ aryl and 5- to        10-membered heteroaryl are optionally substituted with one or        more substituents;    -   (iv) —C(O)C₁₋₆ alkylene-C(O)OR¹⁸, wherein R¹⁸ is H or C₁₋₆alkyl        optionally substituted with one or more substituents;    -   (v) —C(O)C₁₋₆ alkylene-N(R²⁰)C(O)R¹⁹, wherein R¹⁹ is selected        from the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally        substituted with one or more substituents, and wherein the C₆₋₁₀        aryl and 5- to 10-membered heteroaryl are optionally substituted        with one or more substituents, and wherein R²⁰ is H or C₁₋₆        alkyl;    -   (vi) —C(O)C₁₋₆ alkylene-NR²¹R²², wherein each of R²¹ and R²² is        independently selected from the group consisting of H,        C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein        the C₁₋₆alkyl is optionally substituted with one or more        substituents, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents;    -   (vii) —C(O)C₁₋₆ alkylene-C(O)NR²³R²⁴, wherein each of R²³ and        R²⁴ is independently selected from the group consisting of H,        C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein        the C₁₋₆alkyl is optionally substituted with one or more        substituents, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents;    -   (viii) —C(O)C₁₋₆ alkylene-S(O)₂R²⁵, wherein R²⁵ is selected from        the group consisting of C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally        substituted with one or more substituents, and wherein the C₆₋₁₀        aryl and 5- to 10-membered heteroaryl are optionally substituted        with one or more substituents; and    -   (ix) —S(O)₂R²⁶, wherein R²⁶ is selected from the group        consisting of C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-membered        heteroaryl, wherein the C₁₋₆alkyl is optionally substituted with        one or more substituents, and wherein the C₆₋₁₀ aryl and 5- to        10-membered heteroaryl are optionally substituted with one or        more substituents;        R¹ is selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀        aryl, 5- to 10-membered heteroaryl, —C₁₋₆ alkylene(C₆₋₁₀ aryl)        and —C₁₋₆alkylene(5- to 10-membered heteroaryl), wherein the        C₁₋₆alkyl, the C₆₋₁₀ aryl, the C₆₋₁₀ aryl of —C₁₋₆alkylene(C₆₋₁₀        aryl), the 5- to 10-membered heteroaryl and the 5- to        10-membered heteroaryl of —C₁₋₆alkylene(5- to 10-membered        heteroaryl) are optionally substituted with one or more        substituents, and wherein the C₁₋₆alkylene of        —C₁₋₆alkylene(C₆₋₁₀ aryl) and —C₁₋₆ alkylene(5- to 10-membered        heteroaryl) is optionally substituted with one or more        substituents;        R³ is selected from the group consisting of:    -   (i) C₆₋₁₀ aryl which is optionally substituted with one or more        substituents;    -   (ii) 5- to 10-membered heteroaryl which is optionally        substituted with one or more substituents;    -   (iii) —C₁₋₆alkylene(C₆₋₁₀ aryl), wherein the C₆₋₁₀ aryl is        optionally substituted with one or more substituents, and        wherein the C₁₋₆ alkylene is optionally substituted with one or        more substituents;    -   (iv) —C₁₋₆alkylene(5- to 10-membered heteroaryl), wherein the 5-        to 10-membered heteroaryl is optionally substituted with one or        more substituents, and wherein the C₁₋₆ alkylene is optionally        substituted with one or more substituents;    -   (v) —C₁₋₆ alkylene-NR²⁷C(O)R²⁸, wherein:        -   R²⁷ is H or C₁₋₆alkyl;        -   R²⁸ is selected from the group consisting of C₁₋₆alkyl,            C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, and —NR²⁹R³⁰,            wherein the C₁₋₆alkyl is optionally substituted with one or            more substituents, and wherein the C₆₋₁₀ aryl and 5- to            10-membered heteroaryl are optionally substituted with one            or more substituents; and        -   wherein each of R²⁹ and R³⁰ is independently selected from            the group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to            10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally            substituted with one or more substituents, and wherein the            C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally            substituted with one or more substituents;    -   (vi) —(C₆₋₁₀ arylene)-C(O)NR³¹R³² or —C₁₋₆ alkylene-(C₆₋₁₀        arylene)-C(O)NR³¹R³², wherein each of R³¹ and R³² is        independently selected from the group consisting of H, C₁₋₆        alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the        C₁₋₆ alkyl is optionally substituted with one or more        substituents, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents;    -   (vii) —(C₆₋₁₀ arylene)-NR³³R³⁴ or —C₁₋₆ alkylene-(C₆₋₁₀        arylene)-NR³³R³⁴, wherein:        -   each of R³³ and R³⁴ is independently selected from the group            consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, 5- to 10-membered            heteroaryl, —C(O)R³⁵, —C(O)NR³⁶R³⁷, and —SO₂R³⁸, wherein the            C₁₋₆alkyl is optionally substituted with one or more            substituents, and wherein the C₆₋₁₀ aryl and 5- to            10-membered heteroaryl are optionally substituted with one            or more substituents;        -   R³⁵ is selected from the group consisting of C₁₋₆alkyl,            C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, and 5- to            10-membered heterocycloalkyl, wherein the C₁₋₆alkyl is            optionally substituted with one or more substituents, and            wherein the C₆₋₁₀ aryl, 5-to 10-membered heteroaryl, and 5-            to 10-membered heterocycloalkyl are optionally substituted            with one or more substituents;        -   each of R³⁶ and R³⁷ is independently selected from the group            consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to            10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally            substituted with one or more substituents, and wherein the            C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally            substituted with one or more substituents; and        -   R³⁸ is selected from the group consisting of C₁₋₆alkyl,            C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the            C₁₋₆alkyl is optionally substituted with one or more            substituents, and wherein the C₆₋₁₀ aryl and 5- to            10-membered heteroaryl are optionally substituted with one            or more substituents;    -   (viii) —(C₆₋₁₀ arylene)-SO₂NR³⁹R⁴⁰ or —C₁₋₆ alkylene-(C₆₋₁₀        arylene)-SO₂NR³⁹R⁴⁰, wherein each of R³⁹ and R⁴⁰ is        independently selected from the group consisting of H, C₁₋₆        alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the        C₁₋₆ alkyl is optionally substituted with one or more        substituents, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents;    -   (ix) —(C₆₋₁₀ arylene)-(C₁₋₆ alkylene)-NR⁴¹R⁴² or —C₁₋₆        alkylene-(C₆₋₁₀ arylene)-(C₁₋₆ alkylene)-NR⁴¹R⁴², wherein:        -   each of R⁴¹ and R⁴² is independently selected from the group            consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, 5- to 10-membered            heteroaryl, —C(O)R⁴³, and —C(O)NR⁴⁴R⁴⁵, wherein the            C₁₋₆alkyl is optionally substituted with one or more            substituents, and wherein the C₆₋₁₀ aryl and 5- to            10-membered heteroaryl are optionally substituted with one            or more substituents;        -   R⁴³ is selected from the group consisting of C₁₋₆alkyl,            C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the            C₁₋₆alkyl is optionally substituted with one or more            substituents, and wherein the C₆₋₁₀ aryl and 5- to            10-membered heteroaryl are optionally substituted with one            or more substituents; and        -   each of R⁴⁴ and R⁴⁵ is independently selected from the group            consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to            10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally            substituted with one or more substituents, and wherein the            C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally            substituted with one or more substituents;    -   (x) —(C₆₋₁₀ arylene)-OR⁴⁶ or —C₁₋₆ alkylene-(C₆₋₁₀        arylene)-OR⁴⁶, wherein R⁴⁶ is selected from the group consisting        of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5-to 10-membered heteroaryl,        wherein the C₁₋₆alkyl is optionally substituted with one or more        substituents, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents; and    -   (xi) —C₁₋₆ alkylene-(C₆₋₁₀ arylene)-N(R⁴⁷)—C(O)—CHR⁴⁸—NR⁴⁹R⁵⁰,        wherein R⁴⁷ is H or CH₃, R⁴⁸ is H or C₁₋₆alkyl optionally        substituted with one or more substituents each independently        selected from the group consisting of hydroxyl, —COOH, —NH₂,        —C(O)NH₂, and —N(H)C(O)NH₂, and each of R⁴⁹ and R⁵⁰ is        independently H, CH₃ or acetyl;        R⁴ is selected from the group consisting of:    -   (i) —C₁₋₆ alkylene-N(R⁵³)C(O)NR⁵¹R⁵², wherein each of R⁵¹ and        R⁵² is independently selected from the group consisting of H,        C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein        the C₁₋₆alkyl is optionally substituted with one or more        substituents, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents, and wherein R⁵³ is H or C₁₋₆ alkyl;    -   (ii) —C₁₋₆ alkylene-N(R⁵⁵)C(O)R⁵⁴, wherein R⁵⁴ is selected from        the group consisting of C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, wherein the C₁₋₆ alkyl is optionally        substituted with one or more substituents, and wherein the C₆₋₁₀        aryl and 5- to 10-membered heteroaryl are optionally substituted        with one or more substituents, and wherein R⁵⁵ is H or C₁₋₆        alkyl;    -   (iii) —(C₆₋₁₀ arylene)-C(O)NR⁵⁶R⁵⁷ or —C₁₋₆ alkylene-(C₆₋₁₀        arylene)-C(O)NR⁵⁶R⁵⁷, wherein each of R⁵⁶ and R⁵⁷ is        independently selected from the group consisting of H,        C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein        the C₁₋₆ alkyl is optionally substituted with one or more        substituents, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents;    -   (iv) —(C₆₋₁₀ arylene)-N(R⁵⁹)C(O)R⁵⁸ or —C₁₋₆ alkylene-(C₆₋₁₀        arylene)-N(R⁵⁹)C(O)R⁵⁸, wherein R⁵⁸ is selected from the group        consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, 5- to 10-membered        heteroaryl, and 5- to 10-membered heterocycloalkyl, wherein the        C₁₋₆alkyl is optionally substituted with one or more        substituents, and wherein the C₆₋₁₀ aryl, 5- to 10-membered        heteroaryl, and 5- to 10-membered heterocycloalkyl are        optionally substituted with one or more substituents, and        wherein R⁵⁹ is H or C₁₋₆alkyl;    -   (v) —(C₆₋₁₀ arylene)-N(R⁶¹)C(O)NR⁶⁰R⁶¹ or —C₁₋₆ alkylene-(C₆₋₁₀        arylene)-N(R⁶²)C(O)NR⁶⁰R⁶¹, wherein each of R⁶⁰ and R⁶¹ is        independently selected from the group consisting of H, C₁₋₆        alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the        C₁₋₆ alkyl is optionally substituted with one or more        substituents, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents, and wherein R⁶² is H or C₁₋₆ alkyl;    -   (vi) —(C₆₋₁₀ arylene)-N(R⁶⁴)SO₂R⁶³ or —C₁₋₆ alkylene-(C₆₋₁₀        arylene)-N(R⁶⁴)SO₂R⁶³, wherein R⁶³ is selected from the group        consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-membered        heteroaryl, wherein the C₁₋₆alkyl is optionally substituted with        one or more substituents, and wherein the C₆₋₁₀ aryl and 5- to        10-membered heteroaryl are optionally substituted with one or        more substituents, and wherein R⁶⁴ is H or C₁₋₆ alkyl;    -   (vii) —(C₆₋₁₀ arylene)-SO₂NR⁶⁵R⁶⁶ or —C₁₋₆ alkylene-(C₆₋₁₀        arylene)-SO₂NR⁶⁵R⁶⁶, wherein each of R⁶⁵ and R⁶⁶ is        independently selected from the group consisting of H,        C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein        the C₁₋₆alkyl is optionally substituted with one or more        substituents, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents;    -   (viii) —(C₆₋₁₀ arylene)-(C₁₋₆ alkylene)-NR⁶⁷R⁶⁸ or —C₁₋₆        alkylene-(C₆₋₁₀ arylene)-(C₁₋₆ alkylene)-NR⁶⁷R⁶⁸, wherein:        -   each of R⁶⁷ and R⁶⁸ is independently selected from the group            consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, 5- to 10-membered            heteroaryl, —C(O)R⁶⁹, and —C(O)NR⁷⁰R⁷¹, wherein the            C₁₋₆alkyl is optionally substituted with one or more            substituents, and wherein the C₆₋₁₀ aryl and 5- to            10-membered heteroaryl are optionally substituted with one            or more substituents;        -   R⁶⁹ is selected from the group consisting of C₁₋₆alkyl,            C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the            C₁₋₆alkyl is optionally substituted with one or more            substituents, and wherein the C₆₋₁₀ aryl and 5- to            10-membered heteroaryl are optionally substituted with one            or more substituents; and        -   each of R⁷⁰ and R⁷¹ is independently selected from the group            consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to            10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally            substituted with one or more substituents, and wherein the            C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally            substituted with one or more substituents;    -   (ix) —(C₆₋₁₀ arylene)-NR⁷²R⁷³ or —C₁₋₆ alkylene-(C₆₋₁₀        arylene)-NR⁷²R⁷³, wherein each of R⁷² and R⁷³ is independently        selected from the group consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl,        and 5- to 10-membered heteroaryl, wherein the C₁₋₆ alkyl is        optionally substituted with one or more substituents, and        wherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are        optionally substituted with one or more substituents;    -   (x) —(C₆₋₁₀ arylene)-OR⁷⁴ or —C₁₋₆ alkylene-(C₆₋₁₀        arylene)-OR⁷⁴, wherein R⁷⁴ is selected from the group consisting        of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5-to 10-membered heteroaryl,        wherein the C₁₋₆alkyl is optionally substituted with one or more        substituents, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents;    -   (xi) —C₁₋₆ alkylene-(C₆₋₁₀ arylene)-N(R⁷⁵)—C(O)—CHR⁷⁶—NR⁷⁷R⁷⁸,        wherein R⁷⁵ is H or CH₃, R⁷⁶ is H or C₁₋₆alkyl optionally        substituted with one or more substituents each independently        selected from the group consisting of hydroxyl, —COOH, —NH₂,        —C(O)NH₂, and —N(H)C(O)NH₂, and each of R⁷⁷ and R⁷⁸ is        independently H, CH₃ or acetyl; and    -   (xii) —C₁₋₆ alkylene-(C₆₋₁₀ arylene)-CN;        R⁵ is selected from the group consisting of:    -   (i) —NR⁷⁹R⁸⁰, wherein each of R⁷⁹ and R⁸⁰ is independently        selected from the group consisting of H, C₁₋₆ alkyl, —C(O)R⁸¹,        and —C(═NR⁸²)NR⁸³R⁸⁴, or R⁷⁹ and R⁸⁰, together with the N atom        to which they are attached, form 5- to 10-membered heteroaryl or        5- to 10-membered heterocycloalkyl, wherein the C₁₋₆ alkyl is        optionally substituted with one or more substituents, and        wherein the 5- to 10-membered heteroaryl and 5- to 10-membered        heterocycloalkyl are optionally substituted with one or more        substituents,        -   R⁸¹ is selected from the group consisting of H, —NH₂, C₁₋₁₆            alkyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, and 5- to 10-membered            heteroaryl; and        -   each of R⁸², R⁸³, and R⁸⁴ is independently selected from the            group consisting of H, C₁₋₁₆ alkyl, C₁₋₆ haloalkyl, C₆₋₁₀            aryl, and 5- to 10-membered heteroaryl; and    -   (ii) —N⁺R⁸⁵R⁸⁶R⁸⁷, wherein each of R⁸⁵, R⁸⁶, and R⁸⁷ is        independently C₁₋₆ alkyl;        n¹ is 1, 2, 3, 4, 5, or 6; R⁶ is C₁₋₆ alkyl optionally        substituted with one or more substituents; R⁸ is selected from        the group consisting of C₁₋₆ alkyl, C₆₋₁₀ aryl, 5- to        10-membered heteroaryl, —C₁₋₆ alkylene(C₆₋₁₀ aryl) and        —C₁₋₆alkylene(5- to 10-membered heteroaryl), wherein the        C₁₋₆alkyl, the C₆₋₁₀ aryl, the C₆₋₁₀ aryl of —C₁₋₆alkylene(C₆₋₁₀        aryl), the 5- to 10-membered heteroaryl and the 5- to        10-membered heteroaryl of —C₁₋₆alkylene(5- to 10-membered        heteroaryl) are optionally substituted with one or more        substituents, and wherein the C₁₋₆alkylene of        —C₁₋₆alkylene(C₆₋₁₀ aryl) and —C₁₋₆ alkylene(5- to 10-membered        heteroaryl) is optionally substituted with one or more        substituents; R⁹ is H or C₁₋₆ alkyl; R¹⁰ is H or C₁₋₆ alkyl; R¹¹        is H or C₁₋₆ alkyl; R¹² is H or C₁₋₆ alkyl; R¹³ is H or C₁₋₆        alkyl; R¹⁴ is H or C₁₋₆ alkyl; R¹⁵ is H or C₁₋₆ alkyl; and L is        selected from the group consisting of:

wherein X is S or O; and vii)

chiral centre *1 is in the S configuration or the R configuration;chiral centre *2 is in the S configuration or the R configuration;chiral centre *3 is in the S configuration or the R configuration;chiral centre *4 is in the S configuration or the R configuration;chiral centre *5 is in the S configuration or the R configuration;chiral centre *6 is in the S configuration or the R configuration;chiral centre *7 is in the S configuration or the R configuration; andchiral centre *8 is in the S configuration or the R configuration,provided that:

-   -   i) when R^(C) is NH₂, R^(N) is H or —C(O)CH₂N₃, R¹ is

R³ is

R⁵ is NH₂, n¹ is 4, R⁶ is —CH(OH)(CH₃), R⁸ is

each of R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴ and R¹⁵ is H, and L is

then R⁴ is not

and

-   -   ii) when R^(C) is NH₂, R^(N) is H, R¹ is

R³ is

R⁵ is NH₂, n is 4, R⁶ is —CH(CH₃)₂, R⁸ is —CH(OH)(CH₃), each of R⁹, R¹⁰,R¹¹, R¹², R¹³, R¹⁴ and R¹⁵ is H, and L is

then R⁴ is not

In illustrative embodiments of the present invention, a compound asdefined anywhere herein or a pharmaceutically acceptable salt thereofmay be for use in the prevention or treatment of hypoglycemia. Inillustrative embodiments of the present invention, the hypoglycemia maybe insulin-induced hypoglycemia. In illustrative embodiments of thepresent invention, a compound as defined anywhere herein or apharmaceutically acceptable salt thereof may be for use in the treatmentof diabetes.

In illustrative embodiments of the present invention, there is provideda pharmaceutical composition comprising a compound as defined anywhereherein or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable carrier. In illustrative embodiments of thepresent invention, the pharmaceutical composition may be for use in theprevention or treatment of hypoglycemia. In illustrative embodiments ofthe present invention, the hypoglycemia may be insulin-inducedhypoglycemia. In illustrative embodiments of the present invention, thepharmaceutical composition may be for use in the treatment of diabetes.

In illustrative embodiments of the present invention, there is provideda method of inhibiting an activity of an SSTR2 receptor in a subject,the method comprising administering a compound as defined anywhereherein or a pharmaceutically acceptable salt thereof, to a subject inneed thereof. In illustrative embodiments of the present invention,there is provided a method of preventing or treating hypoglycemia in asubject, the method comprising administering a compound as definedanywhere herein or a pharmaceutically acceptable salt thereof, to asubject in need thereof. In illustrative embodiments of the presentinvention, the hypoglycemia is insulin-induced hypoglycemia. Inillustrative embodiments of the present invention, there is provided amethod of treating diabetes in a subject, the method comprisingadministering a compound as defined anywhere herein or apharmaceutically acceptable salt thereof, to a subject in need thereof.

In illustrative embodiments of the present invention, there is provideda use of a compound as defined anywhere herein or a pharmaceuticallyacceptable salt thereof for the prevention or treatment of hypoglycemia.In illustrative embodiments of the present invention, the hypoglycemiais insulin-induced hypoglycemia.

In illustrative embodiments of the present invention, there is provideda use of a compound as defined anywhere herein or a pharmaceuticallyacceptable salt thereof in the treatment of diabetes. In illustrativeembodiments of the present invention, there is provided a use of acompound as defined anywhere herein or a pharmaceutically acceptablesalt thereof in the preparation of a medicament for the prevention ortreatment of hypoglycemia. In illustrative embodiments of the presentinvention, the hypoglycemia is insulin-induced hypoglycemia. Inillustrative embodiments of the present invention, there is provided ause of a compound as defined anywhere herein or a pharmaceuticallyacceptable salt thereof in the preparation of a medicament for thetreatment of diabetes.

In illustrative embodiments of the present invention, there is providedan amino acid selected from the group consisting of:

Other aspects and features of the present invention will become apparentto those ordinarily skilled in the art upon review of the followingdescription of specific embodiments of the invention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a schematic of the study design indicating when animals weremade diabetic with STZ injection (week 0) followed by insulin pelletimplantation (week 1) to control diabetes, then the subsequenthypoglycemic challenges (weeks 2 and 3).

FIG. 2 shows a detailed procedure for the hypoglycemic challenges (FIG.2A—Hypoglycemia Challenge #1; FIG. 2B—Hypoglycemia Challenge #2) and thetiming of measurements and sample collections.

FIG. 3 is a graph showing blood glucose (BG) values measured over timein STZ diabetic Sprague Dawley rats treated with either vehicle control,Compound 4, or Compound 24 in Hypoglycemic Challenge #1. The inset graphprovides measures of the extent of hypoglycemia of the animals from theBG vs time curves as represented by the area under the curve (AUC) forthe blood glucose values over time.

FIG. 4 is a graph showing the time to onset of hypoglycemia of the STZdiabetic Sprague Dawley rats treated with either vehicle control,Compound 4, or Compound 24 in Hypoglycemia Challenge #1.

FIG. 5 is a graph showing the data from FIG. 3, presented as a survivalcurve, indicating the proportion of rats from each group that were inhypoglycemia (defined as the BG threshold of 3.9 mM) as a function oftime.

FIG. 6 is a graph showing the data from FIG. 3, presented as a survivalcurve, indicating the proportion of rats from each group that were insevere hypoglycemia (defined as the BG threshold of 1.9 mM) as afunction of time.

FIGS. 7A and 7B are graphs showing the response of glucagon tohypoglycemia in STZ diabetic Sprague Dawley rats treated with eithervehicle control, Compound 4, or Compound 24 in Hypoglycemia Challenge#1.

FIG. 8 is a graph showing portal blood glucagon concentrations athypoglycemia in STZ diabetic Sprague Dawley rats treated with eithervehicle control, Compound 4, or Compound 24 during HypoglycemiaChallenge #2.

DETAILED DESCRIPTION

As used herein, “optional” or “optionally” means that the subsequentlydescribed event or circumstance may but need not occur, and thedescription includes instances where the event or circumstance occursand instances in which it does not.

If an item is described as being “independently selected” from a group,each item is selected independent of the other(s). Each item thereforemay be the same as or different from the other item(s).

As used herein, the term “substituted,” refers to a group wherein anon-hydrogen substituent is in the place of a hydrogen substituent on acarbon or nitrogen of the group. For example, a substituted alkyl is analkyl group wherein at least one non-hydrogen substituent is in theplace of a hydrogen substituent on the alkyl group. Non-limitingexamples of substituents include halogen, —OH, —NO₂, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)₂, —C₁₋₆ alkyl,haloC₁₋₆ alkyl, aminoC₁₋₆ alkyl, C₆₋₁₀ aryl, 5- to 10-memberedheteroaryl, 5- to 10-membered heterocycloalkyl, C₅₋₁₀ cycloalkyl, azido,—CN, oxo (═O), —COR²⁰⁰ wherein R²⁰⁰ is C₁₋₆ alkyl or C₆₋₁₀ aryl,—CO₂R²⁰¹ wherein R²⁰¹ is H or C₁₋₆ alkyl, —CONR²⁰²R²⁰³ wherein R²⁰² andR²⁰³ is H or C₁₋₆ alkyl, —NR²⁰⁴COR²⁰⁵ wherein R²⁰⁴ is H or C₁₋₆ alkyland R²⁰⁵ is C₁₋₆ alkyl, —SO₂NR²⁰⁶R²⁰⁷ wherein R²⁰⁶ and R²⁰⁷ is H or C₁₋₆alkyl, and —NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸ is H or C₁₋₆ alkyl and R²⁰⁹ isC₁₋₆ alkyl.

A group may be substituted with one or more than one substituentprovided that the normal valency of the group is not exceeded, and thatthe substitution results in a stable compound. For example, if a methylgroup (i.e., CH₃) is substituted, then 1, 2 or 3 hydrogen atoms on thecarbon atom may be replaced with substituents. Where a substituent isattached via a double bond, such as an oxo (═O) substituent, thesubstituent occupies two available valences, so the total number ofother substituents that may be included is reduced by two. If a group isdescribed as being substituted with up to a particular number ofsubstituents, that group may be substituted by up to that particularnumber of substituents provided that the normal valency of the group isnot exceeded, and that the substitution results in a stable compound.Thus, for example, if a group is described as a heteroaryl substitutedwith up to 3 substituents, then any heteroaryl with less than 3substitutable positions would be substituted by up to only as manysubstituents as the heteroaryl has substitutable positions. For example,tetrazolyl (which has only one substitutable position) would besubstituted with up to one substituent. As a further example, if anamino nitrogen is described as being substituted with up to 2substituents, then the nitrogen will be substituted with up to 2substituents if the amino nitrogen is a primary nitrogen, whereas theamino nitrogen will be substituted with up to only 1 substituent if theamino nitrogen is a secondary nitrogen. If there is more than onesubstitution on a group, each substituent may be the same or different,unless otherwise stated.

As used herein, unless specified, the point of attachment of asubstituent can be from any suitable position of the substituent. Forexample, pyridinyl (or pyridyl) can be 2-pyridinyl (or pyridin-2-yl),3-pyridinyl (or pyridin-3-yl), or 4-pyridinyl (or pyridin-4-yl).

When a bond to a substituent is shown to cross a bond connecting twoatoms in a ring, then such substituent may be bonded to any of thering-forming atoms in that ring that are substitutable, unless otherwisespecified or otherwise implicit from the context.

As used herein, the terms “optionally substituted” and “substituted orunsubstituted” may be used interchangeably to indicate that theparticular group being described may have no non-hydrogen substituents(i.e., unsubstituted), or the group may have one or more non-hydrogensubstituents (i.e., substituted).

If substituents are described as being “independently selected” from agroup, each substituent is selected independent of the other(s). Eachsubstituent therefore may be the same as or different from the othersubstituent(s).

As used herein, the term “halo” or “halogen,” by itself or as part ofanother group or substituent, refers to fluorine, chlorine, bromine, oriodine. Fluorine may also be depicted as F, —F or fluoro. Chlorine mayalso be depicted as Cl, —Cl or chloro. Bromine may also be depicted asBr, —Br or bromo. Iodine may also be depicted as I, —I or iodo.

As used herein, the term “alkyl,” by itself or as part of another groupor substituent, refers to a saturated, monovalent aliphatic hydrocarbonradical (i.e., a radical obtained from a hydrocarbon by removal of ahydrogen) having a specified number of carbon atoms. Alkyl includeshydrocarbon radicals having straight or branched chains. The term“C_(x-y) alkyl” refers to an alkyl group comprising a number from x to y(with all individual integers within the range included, includingintegers x and y) of carbon atoms in its carbon skeleton. For example, a“C₁₋₆ alkyl” refers to an alkyl group comprising 1, 2, 3, 4, 5, or 6carbon atom(s) in its carbon skeleton. Non-limiting examples of alkylgroups include methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl,sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, 2-pentyl,3-pentyl, 2-methylbutyl, 3-methylbutyl, 2,3-dimethylpropyl, n-hexyl, and2,3-dimethylbutyl.

Alkyl groups may be optionally substituted. Alkyl groups describedherein as optionally substituted may be substituted by one or moresubstituents, which are selected independently unless otherwiseindicated. Non-limiting examples of substituents for alkyl groupsinclude halogen, —OH, —NO₂, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, —NH₂, —NH(C₁₋₆alkyl), —N(C₁₋₆ alkyl)₂, —C₁₋₆ alkyl, haloC₁₋₆ alkyl, aminoC₁₋₆ alkyl,C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, 5- to 10-memberedheterocycloalkyl, C₅₋₁₀ cycloalkyl, azido, —CN, oxo (═O), —COR²⁰⁰wherein R²⁰⁰ is C₁₋₆ alkyl or C₆₋₁₀ aryl, —CO₂R²⁰¹ wherein R²⁰¹ is H orC₁₋₆ alkyl, —CONR²⁰²R²⁰³ wherein R²⁰² and R²⁰³ is H or C₁₋₆ alkyl,—NR²⁰⁴COR²⁰⁵ wherein R²⁰⁴ is H or C₁₋₆ alkyl and R²⁰⁵ is C₁₋₆ alkyl,—SO₂NR²⁰⁶R²⁰⁷ wherein R²⁰⁶ and R²⁰⁷ is H or C₁₋₆ alkyl, and—NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸ is H or C₁₋₆ alkyl and R²⁰⁹ is C₁₋₆ alkyl.Alkyl groups may be substituted by 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10substituent(s).

As used herein, the term “alkylene,” by itself or as part of anothergroup or substituent, refers to a saturated, divalent aliphatichydrocarbon group which can link two other groups together. Alkyleneincludes hydrocarbon groups having straight or branched chains. The openvalences of an alkylene need not be at opposite ends of the chain. Theterm “C_(x-y) alkylene” refers to an alkylene group comprising a numberfrom x to y (with all individual integers within the range included,including integers x and y) of carbon atoms in its carbon skeleton. Forexample, a “C₁₋₆ alkylene” refers to an alkylene group comprising 1, 2,3, 4, 5, or 6 carbon atom(s) in its carbon skeleton. Non-limitingexamples of alkylene include methylene (—CH₂—), 1,2-ethylene (—CH₂CH₂—),1,3-propylene (—CH₂CH₂CH₂—), 1,4-butylene (—CH₂CH₂CH₂CH₂—), —CH(Me)—,and —C(Me)₂—. Alkylene may also be depicted as —(CH₂)_(n)— wherein n is1, 2, 3, 4, 5, or 6, or —(CR′R″)_(n′)— wherein R′ and R″ are H orC₁₋₆alkyl and n′ is 1, 2, 3, 4, 5, or 6.

Alkylene groups may be optionally substituted. Alkylene groups describedherein as optionally substituted may be substituted by one or moresubstituents, which are selected independently unless otherwiseindicated. Non-limiting examples of substituents for alkylene groupsinclude halogen, —OH, —NO₂, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, —NH₂, —NH(C₁₋₆alkyl), —N(C₁₋₆ alkyl)₂, —C₁₋₆ alkyl, haloC₁₋₆ alkyl, aminoC₁₋₆ alkyl,C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, 5- to 10-memberedheterocycloalkyl, C₅₋₁₀ cycloalkyl, azido, —CN, oxo (═O), —COR²⁰⁰wherein R²⁰⁰ is C₁₋₆ alkyl or C₆₋₁₀ aryl, —CO₂R²⁰¹ wherein R²⁰¹ is H orC₁₋₆ alkyl, —CONR²⁰²R²⁰³ wherein R²⁰² and R²⁰³ is H or C₁₋₆ alkyl,—NR²⁰⁴COR²⁰⁵ wherein R²⁰⁴ is H or C₁₋₆ alkyl and R²⁰⁵ is C₁₋₆ alkyl,—SO₂NR²⁰⁶R²⁰⁷ wherein R²⁰⁶ and R²⁰⁷ is H or C₁₋₆ alkyl, and—NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸ is H or C₁₋₆ alkyl and R²⁰⁹ is C₁₋₆ alkyl.Alkylene groups may be substituted by 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10substituent(s).

As used herein, the term “alkoxy,” by itself or as part of another groupor substituent, refers to an alkyl group that is single bonded to anoxygen atom. The point of attachment of an alkoxy group to the basemolecule is through the oxygen atom. An alkoxy group may be depicted as—O— alkyl. The alkoxy group may contain a straight or branched chain.The term “C_(x-y) alkoxy” refers to an alkoxy group comprising from x toy (with all individual integers within the range included, includingintegers x and y) of carbon atoms. For example, the term “C₁₋₆ alkoxy”refers to an alkoxy group comprising 1, 2, 3, 4, 5, or 6 carbon atom(s).Non-limiting examples of alkoxy groups include methoxy, ethoxy, propoxy,butoxy, and hexyloxy.

As used herein, the term “aryl,” by itself or as part of another groupor substituent, refers to a monocyclic ring or a fused bicyclic orpolycyclic ring system, wherein the monocyclic ring contains aconjugated pi-electron system or at least one ring of the fused ringsystem contains: (i) a conjugated pi-electron system; and (ii) aring-forming carbon atom that is the point of attachment to the basemolecule. A ring-forming carbon atom of a monocyclic ring may not bereplaced by a ring-forming heteroatom. A ring-forming carbon atom of afused ring system may be replaced by a ring-forming heteroatom selectedfrom N, O and S; however, if a fused ring system contains anyring-forming heteroatoms, the ring-forming heteroatoms are not containedin the ring that contains the ring-forming carbon atom that is the pointof attachment to the base molecule. The monocyclic ring or fused ringsystem may contain from 6 to 14 ring-forming atoms, where ring-formingatom includes both ring-forming carbon atoms and heteroatoms. The term“C_(x-y) aryl” refers to a monocyclic ring or fused ring systemcomprising a number from x to y (with all individual integers within therange included, including integers x and y) of ring-forming atoms. Forexample, a “C₆₋₁₀ aryl” refers to a monocyclic ring or fused ring systemcomprising 6, 7, 8, 9 or 10 ring-forming atoms. As a further example,where an aryl group contains any ring-forming heteroatoms, “C₆₋₁₀ aryl”refers to a fused ring system comprising 6, 7, 8, 9 or 10 ring-formingatoms, where ring-forming atom includes both ring-forming carbon atomsand heteroatoms. Fused bicyclic or polycyclic ring systems include afused ring system comprising an aromatic ring fused to: (i) one or morearomatic rings; ii) one or more non-aromatic cycloalkyl rings; (iii) oneor more non-aromatic heterocycloalkyl rings; (iv) one or moreheteroaromatic rings; or (v) any combination or subcombination of (i),(ii), (iii), and (iv). The point of attachment to the base molecule onan aryl group is a ring-forming carbon atom. For greater clarity, wherean aryl group is a fused ring system, the point of attachment to thebase molecule on the fused ring system is a ring-forming carbon atom ofan aromatic ring of the fused ring system, wherein the aromatic ringdoes not contain any ring-forming heteroatoms. Non-limiting examples ofaryl groups include phenyl, naphthyl, anthracyl, phenanthrenyl, indanyl,indenyl, and tetrahydronaphthyl.

Aryl groups may be optionally substituted. Aryl groups described hereinas optionally substituted may be substituted by one or moresubstituents, which are selected independently unless otherwiseindicated. Non-limiting examples of substituents for aryl groups includehalogen, —OH, —NO₂, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, —NH₂, —NH(C₁₋₆ alkyl),—N(C₁₋₆ alkyl)₂, —C₁₋₆ alkyl, haloC₁₋₆ alkyl, aminoC₁₋₆ alkyl, C₆₋₁₀aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocycloalkyl,C₅₋₁₀ cycloalkyl, azido, —CN, oxo (═O), —COR²⁰⁰ wherein R²⁰⁰ is C₁₋₆alkyl or C₆₋₁₀ aryl, —CO₂R²⁰¹ wherein R²⁰¹ is H or C₁₋₆ alkyl,—CONR²⁰²R²⁰³ wherein R²⁰² and R²⁰³ is H or C₁₋₆ alkyl, —NR²⁰⁴COR²⁰⁵wherein R²⁰⁴ is H or C₁₋₆ alkyl and R²⁰⁵ is C₁₋₆ alkyl, —SO₂NR²⁰⁶R²⁰⁷wherein R²⁰⁶ and R²⁰⁷ is H or C₁₋₆ alkyl, and —NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸is H or C₁₋₆ alkyl and R²⁰⁹ is C₁₋₆ alkyl. Aryl groups may besubstituted by 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 substituent(s).

As used herein, the term “arylene,” by itself or as part of anothergroup or substituent, refers to a divalent form of an aryl group asdefined herein. Arylene groups may be optionally substituted by one ormore substituents, which are selected independently unless otherwiseindicated. Non-limiting examples of substituents for arylene groupsinclude halogen, —OH, —NO₂, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, —NH₂, —NH(C₁₋₆alkyl), —N(C₁₋₆ alkyl)₂, —C₁₋₆ alkyl, haloC₁₋₆ alkyl, aminoC₁₋₆ alkyl,C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, 5- to 10-memberedheterocycloalkyl, C₅₋₁₀ cycloalkyl, azido, —CN, oxo (═O), —COR²⁰⁰wherein R²⁰⁰ is C₁₋₆ alkyl or C₆₋₁₀ aryl, —CO₂R²⁰¹ wherein R²⁰¹ is H orC₁₋₆ alkyl, —CONR²⁰²R²⁰³ wherein R²⁰² and R²⁰³ is H or C₁₋₆ alkyl,—NR²⁰⁴COR²⁰⁵ wherein R²⁰⁴ is H or C₁₋₆ alkyl and R²⁰⁵ is C₁₋₆ alkyl,—SO₂NR²⁰⁶R²⁰⁷ wherein R²⁰⁶ and R²⁰⁷ is H or C₁₋₆ alkyl, and—NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸ is H or C₁₋₆ alkyl and R²⁰⁹ is C₁₋₆ alkyl.Arylene groups may be substituted by 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10substituent(s).

As used herein, the term “heteroaryl,” by itself or as part of anothergroup or substituent, refers to a monocyclic ring or a fused bicyclic orpolycyclic ring system, wherein the monocyclic ring contains aconjugated pi-electron system and at least one ring-forming heteroatomselected from N, O and S, or at least one ring of the fused ring systemcontains: (i) a conjugated pi-electron system; (ii) at least onering-forming heteroatom selected from N, O and S; and (iii) aring-forming atom that is the point of attachment to the base molecule.The monocyclic ring or fused ring system may contain from 1, 2, 3, 4, 5,or 6 ring-forming heteroatom(s) selected from N, O and S. The monocyclicring or fused ring system may contain from 5 to 14 ring-forming atoms,where ring-forming atom includes both ring-forming carbon atoms andheteroatoms. The term “x- to y-membered heteroaryl” refers to amonocyclic ring or a fused ring system comprising a number from x to y(with all individual integers within the range included, includingintegers x and y) of ring-forming atoms. For example, a “5- to10-membered heteroaryl” refers to a monocyclic ring or a fused ringsystem comprising 5, 6, 7, 8, 9 or 10 ring-forming atoms. Fused bicyclicor polycyclic ring systems include a fused ring system comprising aheteroaromatic ring fused to: (i) one or more heteroaromatic rings; (ii)one or more aromatic rings; (iii) one or more non-aromatic cycloalkylrings; (iv) one or more non-aromatic heterocycloalkyl rings; or (v) anycombination or subcombination of (i), (ii), (iii), (iv) and (v). Thepoint of attachment to the base molecule on a heteroaryl group is aring-forming atom. For greater clarity, where a heteroaryl group is afused ring system, the point of attachment to the base molecule on thefused ring system is a ring-forming atom of a heteroaromatic ring of thefused ring system. Non-limiting examples of heteroaryl groups includepyrrolyl, furanyl, thiophenyl, pyrazolyl, imidazolyl, isoxazolyl,oxazolyl, isothiazolyl, thiazolyl, 1,2,3-triazolyl, 1,3,4-triazolyl,1-oxa-2,3-diazolyl, 1-oxa-2,4-diazolyl, 1-oxa-2,5-diazolyl,1-oxa-3,4-diazolyl, 1-thia-2,3-diazolyl, 1-thia-2,4-diazolyl,1-thia-2,5-diazolyl, 1-thia-3,4-diazolyl, tetrazolyl, pyridinyl,pyridazinyl, pyrimidinyl, pyrazinyl, benzofuranyl, benzothiophenyl,indolyl, benzimidazolyl, indazolyl, benzotriazolyl,pyrrolo[2,3-b]pyridinyl, pyrrolo[2,3-c]pyridinyl,pyrrolo[3,2-c]pyridinyl, pyrrolo[3,2-b]pyridinyl,imidazo[4,5-b]pyridinyl, imidazo[4,5-c]pyridinyl,pyrazolo[4,3-d]pyidinyl, pyrazolo[4,3-c]pyidinyl,pyrazolo[3,4-c]pyidinyl, pyrazolo[3,4-b]pyidinyl, isoindolyl, indazolyl,purinyl, indolinyl, imidazo[1,2-a]pyridinyl, imidazo[1,5-a]pyridinyl,pyrazolo[1,5-a]pyridinyl, pyrrolo[1-2,b]pyridazinyl,imidazo[1,2-c]pyrimidinyl, quinolinyl, isoquinolinyl, cinnolinyl,azaquinazoline, quinoxalinyl, phthalazinyl, 1,6-naphthyridinyl,1,7-naphthyridinyl, 1,8-naphthyridinyl, 1,5-naphthyridinyl,2,6-naphthyridinyl, 2,7-naphthyridinyl, pyrido[3,2-d]pyrimidinyl,pyrido[4,3-d]pyrimidinyl, pyrido[3,4-d]pyrimidinyl,pyrido[2,3-d]pyrimidinyl, pyrido[2,3-b]pyrazinyl,pyrido[3,4-b]pyrazinyl, pyrimido[5,4-d]pyrimidinyl,pyrazino[2,3-b]pyrazinyl, and pyrimido[4,5-d]pyrimidinyl.

Heteroaryl groups may be optionally substituted. Heteroaryl groupsdescribed herein as optionally substituted may be substituted by one ormore substituents, which are selected independently unless otherwiseindicated. Non-limiting examples of substituents for heteroaryl groupsinclude halogen, —OH, —NO₂, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, —NH₂, —NH(C₁₋₆alkyl), —N(C₁₋₆ alkyl)₂, —C₁₋₆ alkyl, haloC₁₋₆ alkyl, aminoC₁₋₆ alkyl,C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, 5- to 10-memberedheterocycloalkyl, C₅₋₁₀ cycloalkyl, azido, —CN, oxo (═O), —COR²⁰⁰wherein R²⁰⁰ is C₁₋₆ alkyl or C₆₋₁₀ aryl, —CO₂R²⁰¹ wherein R²⁰¹ is H orC₁₋₆ alkyl, —CONR²⁰²R²⁰³ wherein R²⁰² and R²⁰³ is H or C₁₋₆ alkyl,—NR²⁰⁴COR²⁰⁵ wherein R²⁰⁴ is H or C₁₋₆ alkyl and R²⁰⁵ is C₁₋₆ alkyl,—SO₂NR²⁰⁶R²⁰⁷ wherein R²⁰⁶ and R²⁰⁷ is H or C₁₋₆ alkyl, and—NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸ is H or C₁₋₆ alkyl and R²⁰⁹ is C₁₋₆ alkyl.Heteroaryl groups may be substituted by 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10substituent(s).

As used herein, the term “cycloalkyl,” by itself or as part of anothergroup or substituent, refers to a non-aromatic, saturated, monocyclichydrocarbon ring or a spiro, bridged or fused bicyclic or polycyclichydrocarbon ring system, wherein at least one ring of the ring system:(i) is a non-aromatic hydrocarbon ring wherein all unfused ring-formingcarbon atoms are saturated; and (ii) contains a ring-forming carbon atomthat is the point of attachment to the base molecule. A ring-formingcarbon atom of a ring system may be replaced by a ring-formingheteroatom selected from N, O and S; however, if a ring system containsany ring-forming heteroatoms, the ring-forming heteroatoms are notcontained in the ring that contains the ring-forming carbon atom that isthe point of attachment to the base molecule. The monocyclic ring orspiro, bridged or fused polycyclic ring system contains from 5 to 14ring-forming atoms, where ring-forming atom includes both ring-formingcarbon atoms and heteroatoms. The term “C_(x-y) cycloalkyl” refers to amonocyclic ring or spiro, bridged or fused polycyclic ring systemcomprising a number from x to y (with all individual integers within therange included, including integers x and y) of ring-forming atoms. Forexample, a “C₅₋₁₀ cycloalkyl” refers to a monocyclic ring or spiro,bridged or fused polycyclic ring system comprising 5, 6, 7, 8, 9, or 10ring-forming atoms. As a further example, where a cycloalkyl groupcontains any ring-forming heteroatoms, “C₅₋₁₀ cycloalkyl” refers to amonocyclic ring or spiro, bridged or fused polycyclic ring systemcomprising 5, 6, 7, 8, 9, or 10 ring-forming atoms, where ring-formingatom includes both ring-forming carbon atoms and heteroatoms. Fusedbicyclic or polycyclic ring systems include a fused ring systemcomprising a non-aromatic cycloalkyl ring fused to: (i) one or morenon-aromatic cycloalkyl rings; (ii) one or more aromatic rings; (iii)one or more non-aromatic heterocycloalkyl rings; (iv) one or moreheteroaromatic rings; or (v) any combination or subcombination of (i),(ii), (iii), and (iv). The point of attachment to the base molecule on acycloalkyl group is a ring-forming carbon atom. For greater clarity,where a cycloalkyl group is a ring system, the point of attachment tothe base molecule on the ring system is a ring-forming carbon atom of anon-aromatic cycloalkyl ring of the fused ring system, wherein thenon-aromatic cycloalkyl ring does not contain any ring-formingheteroatoms. Non-limiting examples of cycloalkyl groups includecyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl,cyclooctyl, cyclononyl, cyclodecanyl, octahydropentalenyl,octahydro-1H-indenyl, bicyclo[1.1.1]pentanyl, bicyclo[2.2.1]heptanyl,bicyclo[3.2.1]octanyl, bicyclo[5.2.0]nonanyl, adamantanyl, anddecahydronaphthalenyl.

Cycloalkyl groups may be optionally substituted. Cycloalkyl groupsdescribed herein as optionally substituted may be substituted by one ormore substituents, which are selected independently unless otherwiseindicated. Non-limiting examples of substituents for cycloalkyl groupsinclude halogen, —OH, —NO₂, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, —NH₂, —NH(C₁₋₆alkyl), —N(C₁₋₆ alkyl)₂, —C₁₋₆ alkyl, haloC₁₋₆ alkyl, aminoC₁₋₆ alkyl,C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, 5- to 10-memberedheterocycloalkyl, C₅₋₁₀ cycloalkyl, azido, —CN, oxo (═O), —COR²⁰⁰wherein R²⁰⁰ is C₁₋₆ alkyl or C₆₋₁₀ aryl, —CO₂R²⁰¹ wherein R²⁰¹ is H orC₁₋₆ alkyl, —CONR²⁰²R²⁰³ wherein R²⁰² and R²⁰³ is H or C₁₋₆ alkyl,—NR²⁰⁴COR²⁰⁵ wherein R²⁰⁴ is H or C₁₋₆ alkyl and R²⁰⁵ is C₁₋₆ alkyl,—SO₂NR²⁰⁶R²⁰⁷ wherein R²⁰⁶ and R²⁰⁷ is H or C₁₋₆ alkyl, and—NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸ is H or C₁₋₆ alkyl and R²⁰⁹ is C₁₋₆ alkyl.Cycloalkyl groups may be substituted by 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10substituent(s).

As used herein, the term “heterocycloalkyl,” by itself or as part ofanother group or substituent, refers to a non-aromatic saturatedmonocyclic hydrocarbon ring or a spiro, bridged or fused bicyclic orpolycyclic hydrocarbon ring system, wherein the monocyclic ring containsat least one ring-forming heteroatom selected from N, O and S, or atleast one ring of the spiro, bridged or fused ring system: (i) is anon-aromatic hydrocarbon ring wherein all unfused ring-forming atoms aresaturated; (ii) contains at least one ring-forming heteroatom selectedfrom N, O and S; and (iii) contains a ring-forming atom that is thepoint of attachment to the base molecule. The monocyclic ring or spiro,bridged or fused polycyclic ring system may contain from 1, 2, 3, 4, 5,or 6 ring-forming heteroatom(s) selected from N, O and S. The monocyclicring or spiro, bridged or fused polycyclic ring system may contain from5 to 14 ring-forming atoms, where ring-forming atom includes bothring-forming carbon atoms and heteroatoms. The term “x- to y-memberedheterocycloalkyl” refers to a monocyclic ring or spiro, bridged or fusedpolycyclic ring system comprising a number from x to y (with allindividual integers within the range included, including integers x andy) of ring-forming atoms. For example, a “5- to 10-memberedheterocycloalkyl” refers to a monocyclic ring or spiro, bridged or fusedpolycyclic ring system comprising 5 to 10 ring-forming atoms. Fusedbicyclic or polycyclic ring systems include a fused ring systemcomprising a non-aromatic heterocycloalkyl ring fused to: (i) one ormore non-aromatic cycloalkyl rings; (ii) one or more aromatic rings;(iii) one or more non-aromatic heterocycloalkyl rings; (iv) one or moreheteroaromatic rings; or (v) any combination or subcombination of (i),(ii), (iii), and (iv). The point of attachment to the base molecule on aheterocycloalkyl group is a ring-forming atom. For greater clarity,where a heterocycloalkyl group is a ring system, the point of attachmentto the base molecule on the ring system is a ring-forming atom of anon-aromatic heterocycloalkyl ring of the fused ring system.Non-limiting examples of heterocycloalkyl groups include oxiranyl,thiaranyl, aziridinyl, oxetanyl, thiatanyl, azetidinyl,tetrahydrofuranyl, tetrahydrothiophenyl, pyrrolidinyl,tetrahydropyranyl, tetrahydrothiopyranyl, piperidinyl, 1,4-dioxanyl,1,4-oxathianyl, morpholinyl, 1,4-dithianyl, piperazinyl, 1,4-azathianyl,oxepanyl, thiepanyl, azepanyl, 1,4-dioxepanyl, 1,4-oxathiepanyl,1,4-oxaazepanyl, 1,4-dithiepanyl, 1,4-thieazepanyl, and 1,4-diazepanyl.

Heterocycloalkyl groups may be optionally substituted. Heterocycloalkylgroups described herein as optionally substituted may be substituted byone or more substituents, which are selected independently unlessotherwise indicated. Non-limiting examples of substituents forheterocycloalkyl groups include halogen, —OH, —NO₂, C₁₋₆ alkoxy, C₁₋₆haloalkoxy, —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)₂, —C₁₋₆ alkyl,haloC₁₋₆ alkyl, aminoC₁₋₆ alkyl, C₆₋₁₀ aryl, 5- to 10-memberedheteroaryl, 5- to 10-membered heterocycloalkyl, C₅₋₁₀ cycloalkyl, azido,—CN, oxo (═O), —COR²⁰⁰ wherein R²⁰⁰ is C₁₋₆ alkyl or C₆₋₁₀ aryl,—CO₂R²⁰¹ wherein R²⁰¹ is H or C₁₋₆ alkyl, —CONR²⁰²R²⁰³ wherein R²⁰² andR²⁰³ is H or C₁₋₆ alkyl, —NR²⁰⁴COR²⁰⁵ wherein R²⁰⁴ is H or C₁₋₆ alkyland R²⁰⁵ is C₁₋₆ alkyl, —SO₂NR²⁰⁶R²⁰⁷ wherein R²⁰⁶ and R²⁰⁷ is H or C₁₋₆alkyl, and —NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸ is H or C₁₋₆ alkyl and R²⁰⁹ isC₁₋₆ alkyl. Heterocycloalkyl groups may be substituted by 1, 2, 3, 4, 5,6, 7, 8, 9, or 10 substituent(s).

As used herein, the term “-alkylene(aryl)” refers to an aryl group, asdefined herein, which is attached to the base compound through analkylene linker. The term “—C₁₋₆ alkylene(C₆₋₁₀ aryl)” refers to a C₆₋₁₀aryl group, as defined herein, which is attached to the base compoundthrough a C₁₋₆ alkylene linker. The aryl of the -alkylene(aryl) groupmay be optionally substituted. The aryl groups described herein asoptionally substituted may be substituted by one or more substituents,which are selected independently unless otherwise indicated.Non-limiting examples of substituents for the aryl groups or alkylenegroups include halogen, —OH, —NO₂, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, —NH₂,—NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)₂, —C₁₋₆ alkyl, haloC₁₋₆ alkyl, aminoC₁₋₆alkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, 5- to 10-memberedheterocycloalkyl, C₅₋₁₀ cycloalkyl, azido, —CN, oxo (═O), —COR²⁰⁰wherein R²⁰⁰ is C₁₋₆ alkyl or C₆₋₁₀ aryl, —CO₂R²⁰¹ wherein R²⁰¹ is H orC₁₋₆ alkyl, —CONR²⁰²R²⁰³ wherein R²⁰² and R²⁰³ is H or C₁₋₆ alkyl,—NR²⁰⁴COR²⁰⁵ wherein R²⁰⁴ is H or C₁₋₆ alkyl and R²⁰⁵ is C₁₋₆ alkyl,—SO₂NR²⁰⁶R²⁰⁷ wherein R²⁰⁶ and R²⁰⁷ is H or C₁₋₆ alkyl, and—NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸ is H or C₁₋₆ alkyl and R²⁰⁹ is C₁₋₆ alkyl.The aryl groups and alkylene groups may each be substituted by 1, 2, 3,4, 5, 6, 7, 8, 9, or 10 substituent(s).

As used herein, the term “-alkylene(heteroaryl)” refers to a heteroarylgroup, as defined herein, which is attached to the base compound throughan alkylene linker. The term “—C₁₋₆ alkylene(5- to 10-memberedheteroaryl)” refers to a 5- to 10-membered heteroaryl group, as definedherein, which is attached to the base compound through a C₁₋₆ alkylenelinker. The heteroaryl of the -alkylene(heteroaryl) may be optionallysubstituted. The heteroaryl groups described herein as optionallysubstituted may be substituted by one or more substituents, which areselected independently unless otherwise indicated. Non-limiting examplesof substituents for the heteroaryl groups or alkylene groups includehalogen, —OH, —NO₂, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, —NH₂, —NH(C₁₋₆ alkyl),—N(C₁₋₆ alkyl)₂, —C₁₋₆ alkyl, haloC₁₋₆ alkyl, aminoC₁₋₆ alkyl, C₆₋₁₀aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocycloalkyl,C₅₋₁₀ cycloalkyl, azido, —CN, oxo (═O), —COR²⁰⁰ wherein R²⁰⁰ is C₁₋₆alkyl or C₆₋₁₀ aryl, —CO₂R²⁰¹ wherein R²⁰¹ is H or C₁₋₆ alkyl,—CONR²⁰²R²⁰³ wherein R²⁰² and R²⁰³ is H or C₁₋₆ alkyl, —NR²⁰⁴COR²⁰⁵wherein R²⁰⁴ is H or C₁₋₆ alkyl and R²⁰⁵ is C₁₋₆ alkyl, —SO₂NR²⁰⁶R²⁰⁷wherein R²⁰⁶ and R²⁰⁷ is H or C₁₋₆ alkyl, and —NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸is H or C₁₋₆ alkyl and R²⁰⁹ is C₁₋₆ alkyl. The heteroaryl groups andalkylene groups may each be substituted by 1, 2, 3, 4, 5, 6, 7, 8, 9, or10 substituent(s).

As used herein, the symbol “

” indicates the point at which the displayed moiety is attached to theremainder of the molecule. This is sometimes referred to as a point ofattachment. A point of attachment may also be denoted by a dash symbol“—”, for example, —Br.

This invention is based, at least in part, on cyclic peptides that aresomatostatin receptor (SSTR) antagonists. Cyclic peptides of the presentinvention are often selective for a particular SSTR, such as SSTR 2.

Illustrative embodiments of the present invention include a compoundhaving a structure of Formula II:

or a salt thereof, wherein:R^(C) is OH or NH₂;R^(N) is H, CH₃ or acetyl;R¹ is selected from the group consisting of C₆₋₁₀ aryl, 5- to10-membered heteroaryl, —C₁₋₆ alkylene(C₆₋₁₀ aryl) and —C₁₋₆alkylene(5-to 10-membered heteroaryl), wherein the C₆₋₁₀ aryl and the C₆₋₁₀ aryl of—C₁₋₆ alkylene(C₆₋₁₀ aryl) and the 5- to 10-membered heteroaryl and the5- to 10-membered heteroaryl of —C₁₋₆alkylene(5- to 10-memberedheteroaryl) are optionally substituted with one or more substituents,and wherein the C₁₋₆alkylene of —C₁₋₆alkylene(C₆₋₁₀ aryl) and —C₁₋₆alkylene(5- to 10-membered heteroaryl) is optionally substituted withone or more substituents;R³ is selected from the group consisting of:

-   -   (i) C₆₋₁₀ aryl which is optionally substituted with one or more        substituents;    -   (ii) 5- to 10-membered heteroaryl which is optionally        substituted with one or more substituents;    -   (iii) —C₁₋₆alkylene(C₆₋₁₀ aryl), wherein the C₆₋₁₀ aryl is        optionally substituted with one or more substituents, and        wherein the C₁₋₆ alkylene is optionally substituted with one or        more substituents;    -   (iv) —C₁₋₆alkylene(5- to 10-membered heteroaryl), wherein the 5-        to 10-membered heteroaryl is optionally substituted with one or        more substituents, and wherein the C₁₋₆ alkylene is optionally        substituted with one or more substituents;    -   (v) —NR²⁷C(O)R²⁸ or —C₁₋₆ alkylene-NR²⁷C(O)R²⁸, wherein:        -   R²⁷ is H or C₁₋₆alkyl;        -   R²⁸ is selected from the group consisting of C₁₋₆ alkyl,            C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, and —NR²⁹R³⁰,            wherein the C₁₋₆alkyl is optionally substituted with one or            more substituents, and wherein the C₆₋₁₀ aryl and 5- to            10-membered heteroaryl are optionally substituted with one            or more substituents; and        -   wherein each of R²⁹ and R³⁰ is independently selected from            the group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to            10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally            substituted with one or more substituents, and wherein the            C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally            substituted with one or more substituents;    -   (vi) —(C₆₋₁₀ arylene)-C(O)NR³¹R³² or —C₁₋₆ alkylene-(C₆₋₁₀        arylene)-C(O)NR³¹R³², wherein each of R³¹ and R³² is        independently selected from the group consisting of H, C₁₋₆        alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the        C₁₋₆ alkyl is optionally substituted with one or more        substituents, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents;    -   (vii) —(C₆₋₁₀ arylene)-NR³³R³⁴ or —C₁₋₆ alkylene-(C₆₋₁₀        arylene)-NR³³R³⁴, wherein:        -   each of R³³ and R³⁴ is independently selected from the group            consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, 5- to 10-membered            heteroaryl, —C(O)R³⁵, —C(O)NR³⁶R³⁷, and —SO₂R³⁸, wherein the            C₁₋₆alkyl is optionally substituted with one or more            substituents, and wherein the C₆₋₁₀ aryl and 5- to            10-membered heteroaryl are optionally substituted with one            or more substituents;        -   R³⁵ is selected from the group consisting of C₁₋₆alkyl,            C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, and 5- to            10-membered heterocycloalkyl, wherein the C₁₋₆alkyl is            optionally substituted with one or more substituents, and            wherein the C₆₋₁₀ aryl, 5-to 10-membered heteroaryl, and 5-            to 10-membered heterocycloalkyl are optionally substituted            with one or more substituents;        -   each of R³⁶ and R³⁷ is independently selected from the group            consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to            10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally            substituted with one or more substituents, and wherein the            C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally            substituted with one or more substituents; and        -   R³⁸ is selected from the group consisting of C₁₋₆alkyl,            C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the            C₁₋₆alkyl is optionally substituted with one or more            substituents, and wherein the C₆₋₁₀ aryl and 5- to            10-membered heteroaryl are optionally substituted with one            or more substituents;    -   (viii) —(C₆₋₁₀ arylene)-SO₂NR³⁹R⁴⁰ or —C₁₋₆ alkylene-(C₆₋₁₀        arylene)-SO₂NR³⁹R⁴⁰, wherein each of R³⁹ and R⁴⁰ is        independently selected from the group consisting of H, C₁₋₆        alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the        C₁₋₆ alkyl is optionally substituted with one or more        substituents, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents;    -   (ix) —(C₆₋₁₀ arylene)-(C₁₋₆ alkylene)-NR⁴¹R⁴² or —C₁₋₆        alkylene-(C₆₋₁₀ arylene)-(C₁₋₆ alkylene)-NR⁴¹R⁴², wherein:        -   each of R⁴¹ and R⁴² is independently selected from the group            consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, 5- to 10-membered            heteroaryl, —C(O)R⁴³, and —C(O)NR⁴⁴R⁴⁵, wherein the            C₁₋₆alkyl is optionally substituted with one or more            substituents, and wherein the C₆₋₁₀ aryl and 5- to            10-membered heteroaryl are optionally substituted with one            or more substituents;        -   R⁴³ is selected from the group consisting of C₁₋₆alkyl,            C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the            C₁₋₆alkyl is optionally substituted with one or more            substituents, and wherein the C₆₋₁₀ aryl and 5- to            10-membered heteroaryl are optionally substituted with one            or more substituents; and        -   each of R⁴⁴ and R⁴⁵ is independently selected from the group            consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to            10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally            substituted with one or more substituents, and wherein the            C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally            substituted with one or more substituents;    -   (x) —(C₆₋₁₀ arylene)-OR⁴⁶ or —C₁₋₆ alkylene-(C₆₋₁₀        arylene)-OR⁴⁶, wherein R⁴⁶ is selected from the group consisting        of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5-to 10-membered heteroaryl,        wherein the C₁₋₆alkyl is optionally substituted with one or more        substituents, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents; and    -   (xi) —C₁₋₆ alkylene-(C₆₋₁₀ arylene)-N(R⁴⁷)—C(O)—CHR⁴⁸—NR⁴⁹R⁵⁰,        wherein R⁴⁷ is H or CH₃, R⁴⁸ is H or C₁₋₆alkyl optionally        substituted with one or more substituents each independently        selected from the group consisting of hydroxyl, —COOH, —NH₂,        —C(O)NH₂, and —N(H)C(O)NH₂, and each of R⁴⁹ and R⁵⁰ is        independently H, CH₃ or acetyl;        R⁴ is selected from the group consisting of:    -   (i) —N(R⁵³)C(O)NR⁵¹R⁵² or —C₁₋₆ alkylene-N(R⁵³)C(O)NR⁵¹R⁵²,        wherein each of R⁵¹ and R⁵² is independently selected from the        group consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally        substituted with one or more substituents, and wherein the C₆₋₁₀        aryl and 5- to 10-membered heteroaryl are optionally substituted        with one or more substituents, and wherein R⁵³ is H or        C₁₋₆alkyl;    -   (ii) —N(R⁵⁵)C(O)R⁵⁴ or —C₁₋₆ alkylene-N(R⁵⁵)C(O)R⁵⁴, wherein R⁵⁴        is selected from the group consisting of C₁₋₆ alkyl, C₆₋₁₀ aryl,        and 5- to 10-membered heteroaryl, wherein the C₁₋₆ alkyl is        optionally substituted with one or more substituents, and        wherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are        optionally substituted with one or more substituents, and        wherein R⁵⁵ is H or C₁₋₆ alkyl;    -   (iii) —(C₆₋₁₀ arylene)-C(O)NR⁵⁶R⁵⁷ or —C₁₋₆ alkylene-(C₆₋₁₀        arylene)-C(O)NR⁵⁶R⁵⁷, wherein each of R⁵⁶ and R⁵⁷ is        independently selected from the group consisting of H, C₁₋₆        alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the        C₁₋₆ alkyl is optionally substituted with one or more        substituents, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents;    -   (iv) —(C₆₋₁₀ arylene)-N(R⁵⁹)C(O)R⁵⁸ or —C₁₋₆ alkylene-(C₆₋₁₀        arylene)-N(R⁵⁹)C(O)R⁵⁸, wherein R⁵⁸ is selected from the group        consisting of C₁₋₆ alkyl, C₆₋₁₀ aryl, 5- to 10-membered        heteroaryl, and 5- to 10-membered heterocycloalkyl, wherein the        C₁₋₆alkyl is optionally substituted with one or more        substituents, and wherein the C₆₋₁₀ aryl, 5- to 10-membered        heteroaryl, and 5- to 10-membered heterocycloalkyl are        optionally substituted with one or more substituents, and        wherein R⁵⁹ is H or C₁₋₆ alkyl;    -   (v) —(C₆₋₁₀ arylene)-N(R⁶²)C(O)NR⁶⁰R⁶¹ or —C₁₋₆ alkylene-(C₆₋₁₀        arylene)-N(R⁶²)C(O)NR⁶⁰R⁶¹, wherein each of R⁶⁰ and R⁶¹ is        independently selected from the group consisting of H, C₁₋₆        alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the        C₁₋₆alkyl is optionally substituted with one or more        substituents, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents, and wherein R⁶² is H or C₁₋₆ alkyl;    -   (vi) —(C₆₋₁₀ arylene)-N(R⁶⁴)SO₂R⁶³ or —C₁₋₆ alkylene-(C₆₋₁₀        arylene)-N(R⁶⁴)SO₂R⁶³, wherein R⁶³ is selected from the group        consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-membered        heteroaryl, wherein the C₁₋₆alkyl is optionally substituted with        one or more substituents, and wherein the C₆₋₁₀ aryl and 5- to        10-membered heteroaryl are optionally substituted with one or        more substituents, and wherein R⁶⁴ is H or C₁₋₆ alkyl;    -   (vii) —(C₆₋₁₀ arylene)-SO₂NR⁶⁵R⁶⁶ or —C₁₋₆ alkylene-(C₆₋₁₀        arylene)-SO₂NR⁶⁵R⁶⁶, wherein each of R⁶⁵ and R⁶⁶ is        independently selected from the group consisting of H, C₁₋₆        alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the        C₁₋₆ alkyl is optionally substituted with one or more        substituents, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents;    -   (viii) —(C₆₋₁₀ arylene)-(C₁₋₆ alkylene)-NR⁶⁷R⁶⁸ or —C₁₋₆        alkylene-(C₆₋₁₀ arylene)-(C₁₋₆ alkylene)-NR⁶⁷R⁶⁸, wherein:        -   each of R⁶⁷ and R⁶⁸ is independently selected from the group            consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, 5- to 10-membered            heteroaryl, —C(O)R⁶⁹, and —C(O)NR⁷⁰R⁷¹, wherein the            C₁₋₆alkyl is optionally substituted with one or more            substituents, and wherein the C₆₋₁₀ aryl and 5- to            10-membered heteroaryl are optionally substituted with one            or more substituents;        -   R⁶⁹ is selected from the group consisting of C₁₋₆alkyl,            C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the            C₁₋₆alkyl is optionally substituted with one or more            substituents, and wherein the C₆₋₁₀ aryl and 5- to            10-membered heteroaryl are optionally substituted with one            or more substituents; and        -   each of R⁷⁰ and R⁷¹ is independently selected from the group            consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to            10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally            substituted with one or more substituents, and wherein the            C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally            substituted with one or more substituents;    -   (ix) —(C₆₋₁₀ arylene)-NR⁷²R⁷³ or —C₁₋₆ alkylene-(C₆₋₁₀        arylene)-NR⁷²R⁷³, wherein each of R⁷² and R⁷³ is independently        selected from the group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl,        and 5- to 10-membered heteroaryl, wherein the C₁₋₆alkyl is        optionally substituted with one or more substituents, and        wherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are        optionally substituted with one or more substituents;    -   (x) —(C₆₋₁₀ arylene)-OR⁷⁴ or —C₁₋₆ alkylene-(C₆₋₁₀        arylene)-OR⁷⁴, wherein R⁷⁴ is selected from the group consisting        of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl,        wherein the C₁₋₆alkyl is optionally substituted with one or more        substituents, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents; and    -   (xi) —C₁₋₆ alkylene-(C₆₋₁₀ arylene)-N(R⁷⁵)—C(O)—CHR⁷⁶—NR⁷⁷R⁷⁸,        wherein R⁷⁵ is H or CH₃, R⁷⁶ is H or C₁₋₆alkyl optionally        substituted with one or more substituents each independently        selected from the group consisting of hydroxyl, —COOH, —NH₂,        —C(O)NH₂, and —N(H)C(O)NH₂, and each of R⁷⁷ and R⁷⁸ is        independently H, CH₃ or acetyl;        R⁵ is selected from the group consisting of:    -   (i) —NR⁷⁹R⁸⁰, wherein each of R⁷⁹ and R⁸⁰ is independently        selected from the group consisting of H, C₁₋₆ alkyl, —C(O)R⁸¹,        and —C(═NR⁸²)NR⁸³R⁸⁴, or R⁷⁹ and R⁸⁰, together with the N atom        to which they are attached, form 5- to 10-membered heteroaryl or        5- to 10-membered heterocycloalkyl, wherein the C₁₋₆ alkyl is        optionally substituted with one or more substituents, and        wherein the 5- to 10-membered heteroaryl and 5- to 10-membered        heterocycloalkyl are optionally substituted with one or more        substituents,        -   R⁸¹ is selected from the group consisting of H, —NH₂, C₁₋₁₆            alkyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, and 5- to 10-membered            heteroaryl; and        -   each of R⁸², R⁸³, and R⁸⁴ is independently selected from the            group consisting of H, C₁₋₁₆ alkyl, C₁₋₆ haloalkyl, C₆₋₁₀            aryl, and 5- to 10-membered heteroaryl; and    -   (ii) —N⁺R⁸⁵R⁸⁶R⁸⁷, wherein each of R⁸⁵, R⁸⁶, and R⁸⁷ is        independently C₁₋₆ alkyl; n¹ is 1, 2, 3, 4, 5, or 6; R¹² is H or        CH₃; R⁶ is C₁₋₆ alkyl optionally substituted with one or more        substituents; R⁸ is selected from the group consisting of C₆₋₁₀        aryl, 5- to 10-membered heteroaryl, —C₁₋₆alkylene(C₆₋₁₀ aryl)        and —C₁₋₆alkylene(5- to 10-membered heteroaryl), wherein the        C₆₋₁₀ aryl and the C₆₋₁₀ aryl of —C₁₋₆ alkylene(C₆₋₁₀ aryl) and        the 5- to 10-membered heteroaryl and the 5- to 10-membered        heteroaryl of —C₁₋₆alkylene(5- to 10-membered heteroaryl) are        optionally substituted with one or more substituents, and        wherein the C₁₋₆alkylene of —C₁₋₆alkylene(C₆₋₁₀ aryl) and —C₁₋₆        alkylene(5- to 10-membered heteroaryl) is optionally substituted        with one or more substituents; and L is selected from the group        consisting of:

wherein X is S or O; and

chiral centre *1 is in the S configuration or the R configuration;chiral centre *3 is in the S configuration or the R configuration;chiral centre *4 is in the S configuration or the R configuration;chiral centre *5 is in the S configuration; chiral centre *6 is in the Sconfiguration or the R configuration; and chiral centre *8 is in the Sconfiguration or the R configuration, provided that:

when L is

R⁴ is —CH₂-(phenylene)-N(H)C(O)NH₂; R³ is —CH₂-(phenyl) or—CH₂-(phenylene)-N(H)C(O)R³⁵, wherein the phenyl of —CH₂-(phenyl) issubstituted with hydroxy and wherein R³⁵ is2,6-dioxohexahydropyrimidine; R⁵ is NH₂; n¹ is 4; R¹² is H; R⁶ is—CH(OH)(CH₃); and R⁸ is —CH₂-(phenyl) or —CH₂-(napthyl), wherein thephenyl is substituted with hydroxy,

then R₁ is not —CH₂-(phenyl), wherein the phenyl is substituted with —Clor —NO₂.

In accordance with another embodiment, there is provided a compoundhaving a structure of Formula II or a salt thereof, wherein each ofR^(N), R^(C), R¹, R³, R⁴, R⁵, R⁶, R⁸, R₁₂, n₁, L, chiral centre *1,chiral centre *3, chiral centre *4, chiral centre *5, chiral centre *6,and chiral centre *8 is as defined anywhere herein provided that thecompound is not: (i)H-Cpa-cyclo[DCys-Tyr-D-4Aph(Cbm)-Lys-Thr-Cys]-2Nal-NH₂; (ii)H-Cpa-cyclo[DCys-Tyr-D-4Aph(Cbm)-Lys-Thr-Cys]-D-Tyr-NH₂; (iii)H-pNO₂-Phe-cyclo[DCys-Tyr-D-4Aph(Cbm)-Lys-Thr-Cys]-2Nal-NH₂; (iv)H-Cpa-cyclo[DCys-4Aph(Hor)-D-4Aph(Cbm)-Lys-Thr-Cys]-D-Tyr-NH₂; (v)H-pNO₂-Phe-cyclo[DCys-Tyr-D-4Aph(Cbm)-Lys-Thr-Cys]-D-Tyr-NH₂; (vi)H-pNO₂-Phe-cyclo[DCys-4Aph(Hor)-D-4Aph(Cbm)-Lys-Thr-Cys]-D-Tyr-NH₂;(vii) H-Cpa-cyclo[DCys-4Aph(Hor)-D-4Aph(Cbm)-Lys-Thr-Cys]-2Nal-NH₂; and(viii)H-pNO₂-Phe-cyclo[DCys-4Aph(Hor)-D-4Aph(Cbm)-Lys-Thr-Cys]-2Nal-NH₂,wherein DCys and Cys of each of (i), (ii), (iii), (iv), (v), (vi), (vii)and (viii) are linked by

Embodiments of R^(C) and R^(N)

In some embodiments, R^(C) is OH or NHR¹⁶, wherein R¹⁶ is H or C₁₋₆alkyloptionally substituted with one or more substituents. In otherembodiments, R^(C) is OH or NHR¹⁶, wherein R¹⁶ is H or C₁₋₆ alkyloptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, —OH, —NO₂, C₁₋₆ alkoxy,and C₆₋₁₀ aryl. In some embodiments, R^(C) is OH or NHR¹⁶, wherein R¹⁶is H or C₁₋₆alkyl optionally substituted with one or more substituentseach independently selected from the group consisting of halogen, —OH,—NO₂, and C₁₋₆alkoxy. In some embodiments, R^(C) is OH or NHR¹⁶, whereinR¹⁶ is H or C₁₋₆ alkyl. In some embodiments, R^(C) is OH or NHR¹⁶,wherein R¹⁶ is H or C₁₋₅ alkyl. In some embodiments, R^(C) is OH orNHR¹⁶, wherein R¹⁶ is H or C₁₋₄alkyl. In some embodiments, R^(C) is OHor NHR¹⁶, wherein R¹⁶ is H or C₁₋₃ alkyl. In some embodiments, R^(C) isOH or NHR¹⁶, wherein R¹⁶ is H or C₁₋₂ alkyl. In some embodiments, R^(C)is OH or NHR¹⁶, wherein R¹⁶ is H or CH₃. In some embodiments, R^(C) isOH or NH₂. In other embodiments, R^(C) is OH. In other embodiments,R^(C) is NH₂.

In some embodiments, R^(N) is selected from the group consisting of:

-   -   (i) H;    -   (ii) C₁₋₆alkyl;    -   (iii) —C(O)R¹⁷, wherein R¹⁷ is selected from the group        consisting of C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-membered        heteroaryl, wherein the C₁₋₆alkyl is optionally substituted with        one or more substituents, and wherein the C₆₋₁₀ aryl and 5- to        10-membered heteroaryl are optionally substituted with one or        more substituents;    -   (iv) —C(O)C₁₋₆ alkylene-C(O)OR¹⁸, wherein R¹⁸ is H or C₁₋₆alkyl        optionally substituted with one or more substituents;    -   (v) —C(O)C₁₋₆ alkylene-N(R²⁰)C(O)R¹⁹, wherein R¹⁹ is selected        from the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally        substituted with one or more substituents, and wherein the C₆₋₁₀        aryl and 5- to 10-membered heteroaryl are optionally substituted        with one or more substituents, and wherein R²⁰ is H or C₁₋₆        alkyl;    -   (vi) —C(O)C₁₋₆ alkylene-NR²¹R²², wherein each of R²¹ and R²² is        independently selected from the group consisting of H,        C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein        the C₁₋₆alkyl is optionally substituted with one or more        substituents, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents;    -   (vii) —C(O)C₁₋₆ alkylene-C(O)NR²³R²⁴, wherein each of R²³ and        R²⁴ is independently selected from the group consisting of H,        C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein        the C₁₋₆alkyl is optionally substituted with one or more        substituents, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents;    -   (viii) —C(O)C₁₋₆ alkylene-S(O)₂R²⁵, wherein R²⁵ is selected from        the group consisting of C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally        substituted with one or more substituents, and wherein the C₆₋₁₀        aryl and 5- to 10-membered heteroaryl are optionally substituted        with one or more substituents; and (ix) —S(O)₂R²⁶, wherein R²⁶        is selected from the group consisting of C₁₋₆ alkyl, C₆₋₁₀ aryl,        and 5- to 10-membered heteroaryl, wherein the C₁₋₆alkyl is        optionally substituted with one or more substituents, and        wherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are        optionally substituted with one or more substituents.

In other embodiments, R^(N) is selected from the group consisting of:

-   -   (i) H;    -   (ii) C₁₋₆alkyl;    -   (iii) —C(O)R¹⁷, wherein R¹⁷ is selected from the group        consisting of C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-membered        heteroaryl;    -   (iv) —C(O)C₁₋₆ alkylene-C(O)OR¹⁸, wherein R¹⁸ is H or C₁₋₆alkyl;    -   (v) —C(O)C₁₋₆ alkylene-N(R²⁰)C(O)R¹⁹, wherein R¹⁹ is selected        from the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, and wherein R²⁰ is H or C₁₋₆alkyl;    -   (vi) —C(O)C₁₋₆ alkylene-NR²¹R²², wherein each of R²¹ and R²² is        independently selected from the group consisting of H,        C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl;    -   (vii) —C(O)C₁₋₆ alkylene-C(O)NR²³R²⁴, wherein each of R²³ and        R²⁴ is independently selected from the group consisting of H,        C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl;    -   (viii) —C(O)C₁₋₆ alkylene-S(O)₂R²⁵, wherein R²⁵ is selected from        the group consisting of C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl; and    -   (ix) —S(O)₂R²⁶, wherein R²⁶ is selected from the group        consisting of C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-membered        heteroaryl.

In some embodiments, R^(N) is selected from the group consisting of:

-   -   (i) H;    -   (ii) C₁₋₆alkyl;    -   (iii) —C(O)R¹⁷, wherein R¹⁷ is selected from the group        consisting of C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-membered        heteroaryl;    -   (iv) —C(O)C₁₋₃ alkylene-C(O)OR¹⁸, wherein R¹⁸ is H or C₁₋₆alkyl;    -   (v) —C(O)C₁₋₃ alkylene-N(R²⁰)C(O)R¹⁹, wherein R¹⁹ is selected        from the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, and wherein R²⁰ is H or C₁₋₆alkyl;    -   (vi) —C(O)C₁₋₃ alkylene-NR²¹R²², wherein each of R²¹ and R²² is        independently selected from the group consisting of H,        C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl;    -   (vii) —C(O)C₁₋₃ alkylene-C(O)NR²³R²⁴, wherein each of R²³ and        R²⁴ is independently selected from the group consisting of H,        C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl; and    -   (viii) —C(O)C₁₋₃ alkylene-S(O)₂R²⁵, wherein R²⁵ is selected from        the group consisting of C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl.

In other embodiments, R^(N) is selected from the group consisting of H,C₁₋₆alkyl, —C(O)R¹⁷, —C(O)C₁₋₆ alkylene-C(O)OR¹⁸, —C(O)C₁₋₆alkylene-N(R²⁰)C(O)R¹⁹, —C(O)C₁₋₆ alkylene-NR²¹R²², —C(O)C₁₋₆alkylene-C(O)NR²³R²⁴, and —C(O)C₁₋₆ alkylene-S(O)₂R²⁵, wherein R¹⁷ isC₁₋₆ alkyl or 5- to 6-membered heteroaryl, R¹⁸ is C₁₋₆ alkyl, R¹⁹ isC₁₋₆ alkyl or C₆ aryl, each of R²⁰, R²¹, R²², R²³ and R²⁴ is H, and R²⁵is C₆ aryl. In some embodiments, R^(N) is selected from the groupconsisting of H, C₁₋₃ alkyl, —C(O)R¹⁷, —C(O)C₁₋₃ alkylene-C(O)OR¹⁸,—C(O)C₁₋₃ alkylene-N(R²⁰)C(O)R¹⁹, —C(O)C₁₋₃ alkylene-NR²¹R²², —C(O)C₁₋₃alkylene-C(O)NR²³R²⁴, and —C(O)C₁₋₃ alkylene-S(O)₂R²⁵, wherein R¹⁷ isC₁₋₆ alkyl or 5- to 6-membered heteroaryl, R¹⁸ is C₁₋₃ alkyl, R¹⁹ isC₁₋₃ alkyl or C₆ aryl, each of R²⁰, R²¹, R²², R²³ and R²⁴ is H, and R²⁵is C₆ aryl. In some embodiments, R^(N) is H, CH₃ or acetyl. In someembodiments, R^(N) is H or CH₃. In other embodiments, R^(N) is H oracetyl. In other embodiments, R^(N) is CH₃ or acetyl. In someembodiments, R^(N) is H. In other embodiments, R^(N) is CH₃. In stillother embodiments, R^(N) is acetyl.

Those of ordinary skill in the art will appreciate that the cyclicocta-peptides of the instant invention may be functionalized either atthe C- or N-terminus by methods known in the art. For example, twomethods of functionalization include PEGylation and lipidation(Beilstien J. Org. Chem. 2014, 10, 1197-1212). Functionalized peptidesof this nature are also contemplated within the scope of the instantinvention. For example, in some embodiments, R^(C) is —N(H)[CH₂CH₂O]_(n)¹⁶—R²¹⁰, wherein R²¹⁰ may be H or C₁₋₆ alkyl. A person of skill in theart is readily able to ascertain a suitable range of values for n¹⁶ inthe above-referenced formulae for PEG. For example, and withoutlimitation, n¹⁶ may be an integer from 1 to 40. In some embodiments,R^(N) is —C(O)—[CH₂]_(n) ¹⁷—O—[CH₂CH₂O]_(n) ¹⁸—R²¹¹, wherein R²¹ may beH or C₁₋₆ alkyl and n¹⁷ may be an integer from 1 to 6. In anotherembodiment, n¹⁷ may be 1 or 2. In some embodiments, R^(N) is—C(O)—[CH₂CH₂O]_(n) ¹⁹—R²¹¹, wherein R²¹1 may be H or C₁₋₆ alkyl. Inanother embodiment, R^(N) is —[CH₂]_(n) ²⁰—O—[CH₂CH₂O]_(n) ²¹—R²¹²,wherein R²¹² may be H or C₁₋₆ alkyl and n²⁰ may be an integer from 1 to6. In other embodiments, n²⁰ may be 3. In some embodiments, R^(N) is—[CH₂CH₂O]_(n) ²²—R²¹², wherein R²¹² may be H or C₁₋₆ alkyl. A person ofskill in the art is readily able to ascertain a suitable range of valuesfor n¹⁸, n¹⁹, n²¹, and n²² in the above-referenced formulae for PEG. Forexample, and without limitation, each of n¹⁸, n¹⁹, n²¹, and n²² mayindependently be an integer from 1 to 40.

Embodiments of R¹

In some embodiments, R¹ is selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, —C₁₋₆ alkylene(C₆₋₁₀aryl) and —C₁₋₆alkylene(5- to 10-membered heteroaryl), wherein the C₁₋₆alkyl, the C₆₋₁₀ aryl, the C₆₋₁₀ aryl of —C₁₋₆ alkylene(C₆₋₁₀ aryl), the5- to 10-membered heteroaryl and the 5-to 10-membered heteroaryl of—C₁₋₆alkylene(5- to 10-membered heteroaryl) are optionally substitutedwith one or more substituents, and wherein the C₁₋₆alkylene of—C₁₋₆alkylene(C₆₋₁₀ aryl) and —C₁₋₆ alkylene(5- to 10-memberedheteroaryl) is optionally substituted with one or more substituents.

In some embodiments, R¹ is selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, —C₁₋₆ alkylene(C₆₋₁₀aryl) and —C₁₋₆alkylene(5- to 10-membered heteroaryl), wherein the C₁₋₆alkyl, the C₆₋₁₀ aryl, the C₆₋₁₀ aryl of —C₁₋₆ alkylene(C₆₋₁₀ aryl), the5- to 10-membered heteroaryl and the 5-to 10-membered heteroaryl of—C₁₋₆alkylene(5- to 10-membered heteroaryl) are optionally substitutedwith one or more substituents each independently selected from the groupconsisting of halogen, —OH, —NO₂, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, —NH₂,—NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)₂, —C₁₋₆ alkyl, haloC₁₋₆ alkyl, aminoC₁₋₆alkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, 5- to 10-memberedheterocycloalkyl, C₅₋₁₀ cycloalkyl, azido, —CN, —COR²⁰⁰ wherein R²⁰⁰ isC₁₋₆ alkyl or C₆₋₁₀ aryl, —CO₂R²⁰¹ wherein R²⁰¹ is H or C₁₋₆ alkyl,—CONR²⁰²R²⁰³ wherein R²⁰² and R²⁰³ is H or C₁₋₆ alkyl, —NR²⁰⁴COR²⁰⁵wherein R²⁰⁴ is H or C₁₋₆ alkyl and R²⁰⁵ is C₁₋₆ alkyl, —SO₂NR²⁰⁶R²⁰⁷wherein R²⁰⁶ and R²⁰⁷ is H or C₁₋₆ alkyl, and —NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸is H or C₁₋₆ alkyl and R²⁰⁹ is C₁₋₆ alkyl, and wherein the C₁₋₆alkyleneof —C₁₋₆alkylene(C₆₋₁₀ aryl) and —C₁₋₆ alkylene(5- to 10-memberedheteroaryl) is optionally substituted with one or more substituents eachindependently selected from the group consisting of halogen, —OH, —NO₂,C₁₋₆alkoxy, C₁₋₆ haloalkoxy, —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)₂,—C₁₋₆ alkyl, haloC₁₋₆ alkyl, aminoC₁₋₆ alkyl, C₆₋₁₀ aryl, 5- to10-membered heteroaryl, 5- to 10-membered heterocycloalkyl, C₅₋₁₀cycloalkyl, azido, —CN, —COR²⁰⁰ wherein R²⁰⁰ is C₁₋₆ alkyl or C₆₋₁₀aryl, —CO₂R²⁰¹ wherein R²⁰¹ is H or C₁₋₆ alkyl, —CONR²⁰²R²⁰³ whereinR²⁰² and R²⁰³ is H or C₁₋₆ alkyl, —NR²⁰⁴COR²⁰⁵ wherein R²⁰⁴ is H or C₁₋₆alkyl and R²⁰⁵ is C₁₋₆ alkyl, —SO₂NR²⁰⁶R²⁰⁷ wherein R²⁰⁶ and R²⁰⁷ is Hor C₁₋₆ alkyl, and —NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸ is H or C₁₋₆ alkyl andR²⁰⁹ is C₁₋₆ alkyl.

In some embodiments, R¹ is selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, —C₁₋₆ alkylene(C₆₋₁₀aryl) and —C₁₋₆alkylene(5- to 10-membered heteroaryl), wherein the C₁₋₆alkyl, the C₆₋₁₀ aryl, the C₆₋₁₀ aryl of —C₁₋₆ alkylene(C₆₋₁₀ aryl), the5- to 10-membered heteroaryl and the 5-to 10-membered heteroaryl of—C₁₋₆alkylene(5- to 10-membered heteroaryl) are optionally substitutedwith one or more substituents each independently selected from the groupconsisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein theC₁₋₆alkylene of —C₁₋₆ alkylene(C₆₋₁₀ aryl) and —C₁₋₆alkylene(5- to10-membered heteroaryl) is optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen, —OH, —NO₂, C₁₋₆ alkoxy, and C₆₋₁₀ aryl.

In some embodiments, R¹ is selected from the group consisting of C₆₋₁₀aryl, 5- to 10-membered heteroaryl, —C₁— alkylene(C₆₋₁₀ aryl) and—C₁₋₆alkylene(5- to 10-membered heteroaryl), wherein the C₆₋₁₀ aryl andthe C₆₋₁₀ aryl of —C₁₋₆alkylene(C₆₋₁₀ aryl) and the 5- to 10-memberedheteroaryl and the 5- to 10-membered heteroaryl of —C₁₋₆ alkylene(5- to10-membered heteroaryl) are optionally substituted with one or moresubstituents, and wherein the C₁₋₆ alkylene of —C₁₋₆ alkylene(C₆₋₁₀aryl) and —C₁₋₆alkylene(5- to 10-membered heteroaryl) is optionallysubstituted with one or more substituents.

In some embodiments, R¹ is selected from the group consisting of C₆₋₁₀aryl, 5- to 10-membered heteroaryl, —C₁₋₆alkylene(C₆₋₁₀ aryl) and—C₁₋₆alkylene(5- to 10-membered heteroaryl), wherein the C₆₋₁₀ aryl andthe C₆₋₁₀ aryl of —C₁₋₆alkylene(C₆₋₁₀ aryl) and the 5- to 10-memberedheteroaryl and the 5- to 10-membered heteroaryl of —C₁₋₆ alkylene(5- to10-membered heteroaryl) are optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen, —OH, —NO₂, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, —NH₂, —NH(C₁₋₆ alkyl),—N(C₁₋₆ alkyl)₂, —C₁₋₆ alkyl, haloC₁₋₆ alkyl, aminoC₁₋₆ alkyl, C₆₋₁₀aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocycloalkyl,C₅₋₁₀ cycloalkyl, azido, —CN, —COR²⁰⁰ wherein R²⁰⁰ is C₁₋₆ alkyl orC₆₋₁₀ aryl, —CO₂R²⁰¹ wherein R²⁰¹ is H or C₁₋₆ alkyl, —CONR²⁰²R²⁰³wherein R²⁰² and R²⁰³ is H or C₁₋₆ alkyl, —NR²⁰⁴COR²⁰⁵ wherein R²⁰⁴ is Hor C₁₋₆ alkyl and R²⁰⁵ is C₁₋₆ alkyl, —SO₂NR²⁰⁶R²⁰⁷ wherein R²⁰⁶ andR²⁰⁷ is H or C₁₋₆ alkyl, and —NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸ is H or C₁₋₆alkyl and R²⁰⁹ is C₁₋₆ alkyl, and wherein the C₁₋₆alkylene of—C₁₋₆alkylene(C₆₋₁₀ aryl) and —C₁₋₆ alkylene(5- to 10-memberedheteroaryl) is optionally substituted with one or more substituents eachindependently selected from the group consisting of halogen, —OH, —NO₂,C₁₋₆alkoxy, C₁₋₆ haloalkoxy, —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)₂,—C₁₋₆ alkyl, haloC₁₋₆ alkyl, aminoC₁₋₆ alkyl, C₆₋₁₀ aryl, 5- to10-membered heteroaryl, 5- to 10-membered heterocycloalkyl, C₅₋₁₀cycloalkyl, azido, —CN, —COR²⁰⁰ wherein R²⁰⁰ is C₁₋₆ alkyl or C₆₋₁₀aryl, —CO₂R²⁰¹ wherein R²⁰¹ is H or C₁₋₆ alkyl, —CONR²⁰²R²⁰³ whereinR²⁰² and R²⁰³ is H or C₁₋₆ alkyl, —NR²⁰⁴COR²⁰⁵ wherein R²⁰⁴ is H or C₁₋₆alkyl and R²⁰⁵ is C₁₋₆ alkyl, —SO₂NR²⁰⁶R²⁰⁷ wherein R²⁰⁶ and R²⁰⁷ is Hor C₁₋₆ alkyl, and —NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸ is H or C₁₋₆ alkyl andR²⁰⁹ is C₁₋₆ alkyl.

In some embodiments, R¹ is selected from the group consisting of C₆₋₁₀aryl, 5- to 10-membered heteroaryl, —C₁₋₆alkylene(C₆₋₁₀ aryl) and—C₁₋₆alkylene(5- to 10-membered heteroaryl), wherein the C₆₋₁₀ aryl andthe C₆₋₁₀ aryl of —C₁₋₆alkylene(C₆₋₁₀ aryl) and the 5- to 10-memberedheteroaryl and the 5- to 10-membered heteroaryl of —C₁₋₆ alkylene(5- to10-membered heteroaryl) are optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen, —OH, —NO₂, and C₁₋₆ alkoxy, and wherein the C₁₋₆alkylene of—C₁₋₆ alkylene(C₆₋₁₀ aryl) and —C₁₋₆alkylene(5- to 10-memberedheteroaryl) is optionally substituted with one or more substituents eachindependently selected from the group consisting of halogen, —OH, —NO₂,C₁₋₆ alkoxy, and C₆₋₁₀ aryl.

In some embodiments, R¹ is —C₁₋₃ alkylene(C₆₋₁₀ aryl), wherein the C₆₋₁₀aryl is optionally substituted with one or more substituents eachindependently selected from the group consisting of halogen, hydroxy,—NO₂, and C₁₋₆alkoxy, and wherein the C₁₋₃ alkylene is optionallysubstituted with one or more substituents each independently selectedfrom the group consisting of C₆₋₁₀ aryl. In some embodiments, R¹ is—C₁₋₃ alkylene(C₆₋₁₀ aryl), wherein the C₆₋₁₀ aryl is optionallysubstituted with one or more substituents each independently selectedfrom the group consisting of halogen, hydroxy, —NO₂, and C₁₋₆alkoxy. Inother embodiments, R¹ is —C₁₋₃ alkylene(5- to 10-membered heteroaryl),wherein the 5- to 10-membered heteroaryl is optionally substituted withone or more substituents each independently selected from the groupconsisting of halogen, hydroxy, —NO₂, and C₁₋₆alkoxy. In someembodiments, R¹ is —C₁₋₂alkylene(6-membered heteroaryl), wherein the6-membered heteroaryl is optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen, hydroxy, —NO₂, and C₁₋₆alkoxy.

In some embodiments, R¹ is —C₁₋₂ alkylene(C₆₋₁₀ aryl), wherein the C₆₋₁₀aryl is optionally substituted with one or more substituents eachindependently selected from the group consisting of halogen, hydroxyl,—NO₂, and C₁₋₆ alkoxy. In some embodiments, R¹ is —C₁₋₂ alkylene(C₆₋₁₀aryl), wherein the C₆₋₁₀ aryl is optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen, hydroxy and —NO₂. In some embodiments, R¹ is —C₁₋₂alkylene(C₆₋₁₀ aryl), wherein the C₆₋₁₀ aryl is optionally substitutedwith one or more substituents each independently selected from the groupconsisting of halogen and hydroxy. In some embodiments, R¹ is —C₁₋₂alkylene(C₆₋₁₀ aryl), wherein the C₆₋₁₀ aryl is optionally substitutedwith halogen. In some embodiments, R¹ is —C₁₋₂ alkylene(C₆₋₁₀ aryl),wherein the C₆₋₁₀ aryl is optionally substituted with Cl. In someembodiments, R¹ is —C₁₋₂ alkylene(C₆ aryl), wherein the C₆ aryl isoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, hydroxy, —NO₂, and C₁₋₆alkoxy.

In some embodiments, R¹ is —CH₂-phenyl or —CH₂-naphthyl, wherein phenylor naphthyl may be optionally substituted with 1 or 2 substituents eachindependently selected from the group consisting of halogen, hydroxy,—NO₂, and C₁₋₆ alkoxy. In other embodiments, R¹ is —CH₂-phenyl or—CH₂-naphthyl, wherein the phenyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen, hydroxyl, and —NO₂. In some embodiments, R¹ is —CH₂-phenylor —CH₂-naphthyl, wherein the phenyl is optionally substituted with oneor more substituents each independently selected from the groupconsisting of halogen and hydroxyl. In some embodiments, R¹ is—CH₂-phenyl or —CH₂-naphthyl, wherein the phenyl is optionallysubstituted with halogen. In some embodiments, R¹ is —CH₂-phenyl or—CH₂-naphthyl, wherein the phenyl is optionally substituted with Cl.

In some embodiments, R¹ is —CH₂-phenyl, wherein phenyl may be optionallysubstituted with 1 or 2 substituents each independently selected fromthe group consisting of halogen, hydroxy, —NO₂, and C₁₋₆alkoxy. In someembodiments, R¹ is —CH₂-phenyl, wherein phenyl may be optionallysubstituted with 1 or 2 substituents each independently selected fromthe group consisting of halogen, hydroxy, and —NO₂. In some embodiments,R¹ is —CH₂-phenyl, wherein phenyl is unsubstituted. In some embodiments,R¹ is —CH₂-phenyl, wherein phenyl is substituted with 1 or 2substituents each independently selected from the group consisting ofhalogen, hydroxy, —NO₂, and C₁₋₆alkoxy. In some embodiments, R¹ is—CH₂-phenyl, wherein phenyl is substituted with 1 or 2 substituents eachindependently selected from the group consisting of halogen, hydroxy,and —NO₂. In some embodiments, R¹ is —CH₂-phenyl, wherein phenyl issubstituted with 1 or 2 substituents each independently selected fromthe group consisting of halogen and hydroxy.

In some embodiments, R¹ is —CH₂-phenyl, wherein phenyl is substitutedwith 1 or 2 substituents each independently selected from the groupconsisting of —F, —Cl, —Br, and —I. In some embodiments, R¹ is—CH₂-phenyl, wherein phenyl is substituted with 1 or 2 substituents eachof which is —F. In some embodiments, R¹ is —CH₂-phenyl, wherein phenylis substituted with 1 or 2 substituents each of which is —Cl. In someembodiments, R¹ is —CH₂-phenyl, wherein phenyl is substituted with 1 or2 substituents each of which is —Br. In some embodiments, R¹ is—CH₂-phenyl, wherein phenyl is substituted with 1 or 2 substituents eachof which is —I. In some embodiments, R¹ is —CH₂-phenyl, wherein phenylis substituted with 1 substituent which is —F. In some embodiments, R¹is —CH₂-phenyl, wherein phenyl is substituted with 1 substituent whichis —Cl. In some embodiments, R¹ is —CH₂-phenyl, wherein phenyl issubstituted with 1 substituent which is —Br. In some embodiments, R¹ is—CH₂-phenyl, wherein phenyl is substituted with 1 substituent which is—I.

In some embodiments, R¹ is —CH₂-phenyl, wherein phenyl is substitutedwith 1 or 2 substituents each of which is hydroxy. In some embodiments,R¹ is —CH₂-phenyl, wherein phenyl is substituted with 1 substituentwhich is hydroxy. In some embodiments, R¹ is —CH₂-phenyl, wherein phenylis substituted with 1 or 2 substituents each of which is —NO₂. In someembodiments, R¹ is —CH₂-phenyl, wherein phenyl is substituted with 1substituent which is —NO₂. In some embodiments, R¹ is —CH₂-phenyl,wherein phenyl is substituted with 1 or 2 substituents each of which isindependently C₁₋₆alkoxy. In some embodiments, R¹ is —CH₂-phenyl,wherein phenyl is substituted with 1 or 2 substituents each of which isindependently C₁₋₃ alkoxy. In some embodiments, R¹ is —CH₂-phenyl,wherein phenyl is substituted with 1 substituent which is methoxy.

In some embodiments, R¹ is

wherein R⁸⁸ is H, halogen, hydroxyl or C₁₋₃ alkoxy. In some embodiments,R⁸⁸ is H, halogen or hydroxyl. In some embodiments, R⁸⁸ is H, Cl orhydroxyl. In some embodiments, R⁸⁸ is Cl or hydroxyl. In someembodiments, R⁸⁸ is Cl.

In some embodiments, R¹ is —C₁₋₂ alkylene(C₁₀ aryl), wherein the C₁₀aryl is optionally substituted with one or more substituents eachindependently selected from the group consisting of halogen, hydroxyland —NO₂, and C₁₋₆ alkoxy. In some embodiments, R¹ is —CH₂-naphthyl.

In some embodiments, R¹ is selected from the group consisting of—CH₂-pyridinyl, —CH₂— indolyl, —CH₂-thiophenyl, —CH₂-thiazolyl,—CH₂-furanyl, —CH₂-benzothiophenyl, and —CH₂— imidazolyl. In someembodiments, R¹ is —CH₂-pyridinyl. In some embodiments, R¹ is—CH₂-indolyl. In some embodiments, R¹ is —CH₂-thiophenyl. In someembodiments, R¹ is —CH₂-thiazolyl. In some embodiments, R¹ is—CH₂-furanyl. In some embodiments, R¹ is —CH₂-benzothiophenyl. In someembodiments, R¹ is —CH₂-imidazolyl.

Embodiments of R³

In some embodiments, R³ is selected from the group consisting of:

-   -   (i) C₆₋₁₀ aryl which is optionally substituted with one or more        substituents;    -   (ii) 5- to 10-membered heteroaryl which is optionally        substituted with one or more substituents;    -   (iii) —C₁₋₆alkylene(C₆₋₁₀ aryl), wherein the C₆₋₁₀ aryl is        optionally substituted with one or more substituents, and        wherein the C₁₋₆ alkylene is optionally substituted with one or        more substituents;    -   (iv) —C₁₋₆alkylene(5- to 10-membered heteroaryl), wherein the 5-        to 10-membered heteroaryl is optionally substituted with one or        more substituents, and wherein the C₁₋₆ alkylene is optionally        substituted with one or more substituents;    -   (v) —C₁₋₆ alkylene-N(R²²)C(O)R²⁸, wherein:        -   R²² is H or C₁₋₆alkyl;        -   R²⁸ is selected from the group consisting of C₁₋₆alkyl,            C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, and —NR²⁹R³⁰,            wherein the C₁₋₆alkyl is optionally substituted with one or            more substituents, and wherein the C₆₋₁₀ aryl and 5- to            10-membered heteroaryl are optionally substituted with one            or more substituents; and each of R²⁹ and R³⁰ is            independently selected from the group consisting of H, C₁₋₆            alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein            the C₁₋₆alkyl is optionally substituted with one or more            substituents, and wherein the C₆₋₁₀ aryl and 5- to            10-membered heteroaryl are optionally substituted with one            or more substituents;    -   (vi) —(C₆₋₁₀ arylene)-C(O)NR³¹R³² or —C₁₋₆ alkylene-(C₆₋₁₀        arylene)-C(O)NR³¹R³², wherein each of R³¹ and R³² is        independently selected from the group consisting of H, C₁₋₆        alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the        C₁₋₆ alkyl is optionally substituted with one or more        substituents, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents;    -   (vii) —(C₆₋₁₀ arylene)-NR³³R³⁴ or —C₁₋₆ alkylene-(C₆₋₁₀        arylene)-NR³³R³⁴, wherein:        -   each of R³³ and R³⁴ is independently selected from the group            consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, 5- to 10-membered            heteroaryl, —C(O)R³⁵, —C(O)NR³⁶R³⁷, and —SO₂R³⁸, wherein the            C₁₋₆alkyl is optionally substituted with one or more            substituents, and wherein the C₆₋₁₀ aryl and 5- to            10-membered heteroaryl are optionally substituted with one            or more substituents;        -   R³⁵ is selected from the group consisting of C₁₋₆alkyl,            C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, and 5- to            10-membered heterocycloalkyl, wherein the C₁₋₆alkyl is            optionally substituted with one or more substituents, and            wherein the C₆₋₁₀ aryl, 5-to 10-membered heteroaryl, and 5-            to 10-membered heterocycloalkyl are optionally substituted            with one or more substituents;    -   each of R³⁶ and R³⁷ is independently selected from the group        consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-membered        heteroaryl, wherein the C₁₋₆alkyl is optionally substituted with        one or more substituents, and wherein the C₆₋₁₀ aryl and 5- to        10-membered heteroaryl are optionally substituted with one or        more substituents; and        -   R³⁸ is selected from the group consisting of C₁₋₆alkyl,            C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the            C₁₋₆alkyl is optionally substituted with one or more            substituents, and wherein the C₆₋₁₀ aryl and 5- to            10-membered heteroaryl are optionally substituted with one            or more substituents;    -   (viii) —(C₆₋₁₀ arylene)-SO₂NR³⁹R⁴⁰ or —C₁₋₆ alkylene-(C₆₋₁₀        arylene)-SO₂NR³⁹R⁴⁰, wherein each of R³⁹ and R⁴⁰ is selected        from the group consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5-        to 10-membered heteroaryl, wherein the C₁₋₆ alkyl is optionally        substituted with one or more substituents, and wherein the C₆₋₁₀        aryl and 5- to 10-membered heteroaryl are optionally substituted        with one or more substituents;    -   (ix) —(C₆₋₁₀ arylene)-(C₁₋₆ alkylene)-NR⁴¹R⁴² or —C₁₋₆        alkylene-(C₆₋₁₀ arylene)-(C₁₋₆ alkylene)-NR⁴¹R⁴², wherein:        -   each of R⁴¹ and R⁴² is independently selected from the group            consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, 5- to 10-membered            heteroaryl, —C(O)R⁴³, and —C(O)NR⁴⁴R⁴⁵, wherein the            C₁₋₆alkyl is optionally substituted with one or more            substituents, and wherein the C₆₋₁₀ aryl and 5- to            10-membered heteroaryl are optionally substituted with one            or more substituents;        -   R⁴³ is selected from the group consisting of C₁₋₆alkyl,            C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the            C₁₋₆alkyl is optionally substituted with one or more            substituents, and wherein the C₆₋₁₀ aryl and 5- to            10-membered heteroaryl are optionally substituted with one            or more substituents; and        -   each of R⁴⁴ and R⁴⁵ is independently selected from the group            consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to            10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally            substituted with one or more substituents, and wherein the            C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally            substituted with one or more substituents;    -   (x) —(C₆₋₁₀ arylene)-OR⁴⁶ or —C₁₋₆ alkylene-(C₆₋₁₀        arylene)-OR⁴⁶, wherein R⁴⁶ is selected from the group consisting        of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5-to 10-membered heteroaryl,        wherein the C₁₋₆alkyl is optionally substituted with one or more        substituents, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents; and    -   (xi) —C₁₋₆ alkylene-(C₆₋₁₀ arylene)-N(R⁴⁷)—C(O)—CHR⁴⁸—NR⁴⁹R⁵⁰,        wherein R⁴⁷ is H or CH₃, R⁴⁸ is H or C₁₋₆alkyl optionally        substituted with one or more substituents each independently        selected from the group consisting of hydroxyl, —COOH, —NH₂,        —C(O)NH₂, and —N(H)C(O)NH₂, and each of R⁴⁹ and R⁵⁰ is        independently H, CH₃ or acetyl.

In other embodiments, R³ is selected from the group consisting of:

-   -   (i) C₆₋₁₀ aryl which is optionally substituted with one or more        substituents;    -   (ii) 5- to 10-membered heteroaryl which is optionally        substituted with one or more substituents;    -   (iii) —C₁₋₆alkylene(C₆₋₁₀ aryl), wherein the C₆₋₁₀ aryl is        optionally substituted with one or more substituents, and        wherein the C₁₋₆ alkylene is optionally substituted with one or        more substituents;    -   (iv) —C₁₋₆alkylene(5- to 10-membered heteroaryl), wherein the 5-        to 10-membered heteroaryl is optionally substituted with one or        more substituents, and wherein the C₁₋₆ alkylene is optionally        substituted with one or more substituents;    -   (v) —C₁₋₆ alkylene-N(H)C(O)R²⁸, wherein:        -   R²⁸ is selected from the group consisting of C₁₋₆alkyl,            C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, and —NR²⁹R³⁰,            wherein the C₁₋₆alkyl is optionally substituted with one or            more substituents, and wherein the C₆₋₁₀ aryl and 5- to            10-membered heteroaryl are optionally substituted with one            or more substituents; and        -   each of R²⁹ and R³⁰ is independently selected from the group            consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to            10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally            substituted with one or more substituents, and wherein the            C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally            substituted with one or more substituents;    -   (vi) —(C₆₋₁₀ arylene)-C(O)NR³¹R³² or —C₁₋₆ alkylene-(C₆₋₁₀        arylene)-C(O)NR³¹R³², wherein each of R³¹ and R³² is        independently selected from the group consisting of H, C₁₋₆        alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the        C₁₋₆ alkyl is optionally substituted with one or more        substituents, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents;    -   (vii) —(C₆₋₁₀ arylene)-NR³³R³⁴ or —C₁₋₆ alkylene-(C₆₋₁₀        arylene)-NR³³R³⁴, wherein:        -   each of R³³ and R³⁴ is independently selected from the group            consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, 5- to 10-membered            heteroaryl, —C(O)R³⁵, —C(O)NR³⁶R³⁷, and —SO₂R³⁸, wherein the            C₁₋₆alkyl is optionally substituted with one or more            substituents, and wherein the C₆₋₁₀ aryl and 5- to            10-membered heteroaryl are optionally substituted with one            or more substituents;        -   R³⁵ is selected from the group consisting of C₁₋₆alkyl,            C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, and 5- to            10-membered heterocycloalkyl, wherein the C₁₋₆alkyl is            optionally substituted with one or more substituents, and            wherein the C₆₋₁₀ aryl, 5-to 10-membered heteroaryl, and 5-            to 10-membered heterocycloalkyl are optionally substituted            with one or more substituents;        -   each of R³⁶ and R³⁷ is independently selected from the group            consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to            10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally            substituted with one or more substituents, and wherein the            C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally            substituted with one or more substituents; and        -   R³⁸ is selected from the group consisting of C₁₋₆alkyl,            C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the            C₁₋₆alkyl is optionally substituted with one or more            substituents, and wherein the C₆₋₁₀ aryl and 5- to            10-membered heteroaryl are optionally substituted with one            or more substituents;    -   (viii) —(C₆₋₁₀ arylene)-SO₂NR³⁹R⁴⁰ or —C₁₋₆ alkylene-(C₆₋₁₀        arylene)-SO₂NR³⁹R⁴⁰, wherein each of R³⁹ and R⁴⁰ is selected        from the group consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5-        to 10-membered heteroaryl, wherein the C₁₋₆ alkyl is optionally        substituted with one or more substituents, and wherein the C₆₋₁₀        aryl and 5- to 10-membered heteroaryl are optionally substituted        with one or more substituents;    -   (ix) —(C₆₋₁₀ arylene)-(C₁₋₆ alkylene)-NR⁴¹R⁴² or —C₁₋₆        alkylene-(C₆₋₁₀ arylene)-(C₁₋₆ alkylene)-NR⁴¹R⁴², wherein:        -   each of R⁴¹ and R⁴² is independently selected from the group            consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, 5- to 10-membered            heteroaryl, —C(O)R⁴³, and —C(O)NR⁴⁴R⁴⁵, wherein the            C₁₋₆alkyl is optionally substituted with one or more            substituents, and wherein the C₆₋₁₀ aryl and 5- to            10-membered heteroaryl are optionally substituted with one            or more substituents;        -   R⁴³ is selected from the group consisting of C₁₋₆alkyl,            C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the            C₁₋₆alkyl is optionally substituted with one or more            substituents, and wherein the C₆₋₁₀ aryl and 5- to            10-membered heteroaryl are optionally substituted with one            or more substituents; and        -   each of R⁴⁴ and R⁴⁵ is independently selected from the group            consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to            10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally            substituted with one or more substituents, and wherein the            C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally            substituted with one or more substituents;    -   (x) —(C₆₋₁₀ arylene)-OR⁴⁶ or —C₁₋₆ alkylene-(C₆₋₁₀        arylene)-OR⁴⁶, wherein R⁴⁶ is selected from the group consisting        of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5-to 10-membered heteroaryl,        wherein the C₁₋₆alkyl is optionally substituted with one or more        substituents, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents; and    -   (xi) —C₁₋₆ alkylene-(C₆₋₁₀ arylene)-N(R⁴⁷)—C(O)—CHR⁴⁸—N(H)R⁵⁰,        wherein R⁴⁷ is H or CH₃, R⁴⁸ is H or C₁₋₆alkyl optionally        substituted with one or more substituents each independently        selected from the group consisting of hydroxyl, —COOH, —NH₂,        —C(O)NH₂, and —N(H)C(O)NH₂, and R⁵⁰ is H, CH₃ or acetyl.

In some embodiments, R³ is selected from the group consisting of C₆₋₁₀aryl, 5- to 10-membered heteroaryl, —C₁— alkylene(C₆₋₁₀ aryl) and—C₁₋₆alkylene(5- to 10-membered heteroaryl), wherein the C₆₋₁₀ aryl andthe C₆₋₁₀ aryl of —C₁₋₆alkylene(C₆₋₁₀ aryl) and the 5- to 10-memberedheteroaryl and the 5- to 10-membered heteroaryl of —C₁₋₆ alkylene(5- to10-membered heteroaryl) are optionally substituted with one or moresubstituents, and wherein the C₁₋₆ alkylene of —C₁₋₆ alkylene(C₆₋₁₀aryl) and —C₁₋₆alkylene(5- to 10-membered heteroaryl) is optionallysubstituted with one or more substituents.

In some embodiments, R³ is selected from the group consisting of C₆₋₁₀aryl, 5- to 10-membered heteroaryl, —C₁₋₆alkylene(C₆₋₁₀ aryl) and—C₁₋₆alkylene(5- to 10-membered heteroaryl), wherein the C₆₋₁₀ aryl andthe C₆₋₁₀ aryl of —C₁₋₆alkylene(C₆₋₁₀ aryl) and the 5- to 10-memberedheteroaryl and the 5- to 10-membered heteroaryl of —C₁₋₆ alkylene(5- to10-membered heteroaryl) are optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen, —OH, —NO₂, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, —NH₂, —NH(C₁₋₆ alkyl),—N(C₁₋₆ alkyl)₂, —C₁₋₆ alkyl, haloC₁₋₆ alkyl, aminoC₁₋₆ alkyl, C₆₋₁₀aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocycloalkyl,C₅₋₁₀ cycloalkyl, azido, —CN, —COR²⁰⁰ wherein R²⁰⁰ is C₁₋₆ alkyl orC₆₋₁₀ aryl, —CO₂R²⁰¹ wherein R²⁰¹ is H or C₁₋₆ alkyl, —CONR²⁰²R²⁰³wherein R²⁰² and R²⁰³ is H or C₁₋₆ alkyl, —NR²⁰⁴COR²⁰⁵ wherein R²⁰⁴ is Hor C₁₋₆ alkyl and R²⁰⁵ is C₁₋₆ alkyl, —SO₂NR²⁰⁶R²⁰⁷ wherein R²⁰⁶ andR²⁰⁷ is H or C₁₋₆ alkyl, and —NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸ is H or C₁₋₆alkyl and R²⁰⁹ is C₁₋₆ alkyl, and wherein the C₁₋₆alkylene of—C₁₋₆alkylene(C₆₋₁₀ aryl) and —C₁₋₆ alkylene(5- to 10-memberedheteroaryl) is optionally substituted with one or more substituents eachindependently selected from the group consisting of halogen, —OH, —NO₂,C₁₋₆alkoxy, C₁₋₆ haloalkoxy, —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)₂,—C₁₋₆ alkyl, haloC₁₋₆ alkyl, aminoC₁₋₆ alkyl, C₆₋₁₀ aryl, 5- to10-membered heteroaryl, 5- to 10-membered heterocycloalkyl, C₅₋₁₀cycloalkyl, azido, —CN, —COR²⁰⁰ wherein R²⁰⁰ is C₁₋₆ alkyl or C₆₋₁₀aryl, —CO₂R²⁰¹ wherein R²⁰¹ is H or C₁₋₆ alkyl, —CONR²⁰²R²⁰³ whereinR²⁰² and R²⁰³ is H or C₁₋₆ alkyl, —NR²⁰⁴COR²⁰⁵ wherein R²⁰⁴ is H or C₁₋₆alkyl and R²⁰⁵ is C₁₋₆ alkyl, —SO₂NR²⁰⁶R²⁰⁷ wherein R²⁰⁶ and R²⁰⁷ is Hor C₁₋₆ alkyl, and —NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸ is H or C₁₋₆ alkyl andR²⁰⁹ is C₁₋₆ alkyl.

In some embodiments, R³ is selected from the group consisting of C₆₋₁₀aryl, 5- to 10-membered heteroaryl, —C₁₋₆alkylene(C₆₋₁₀ aryl) and—C₁₋₆alkylene(5- to 10-membered heteroaryl), wherein the C₆₋₁₀ aryl andthe C₆₋₁₀ aryl of —C₁₋₆alkylene(C₆₋₁₀ aryl) and the 5- to 10-memberedheteroaryl and the 5- to 10-membered heteroaryl of —C₁₋₆ alkylene(5- to10-membered heteroaryl) are optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein the C₁₋₆alkylene of—C₁₋₆ alkylene(C₆₋₁₀ aryl) and —C₁₋₆alkylene(5- to 10-memberedheteroaryl) is optionally substituted with one or more substituents eachindependently selected from the group consisting of halogen, —OH, —NO₂,C₁₋₆ alkoxy, and C₆₋₁₀ aryl.

In some embodiments, R³ is —C₁₋₃ alkylene(C₆₋₁₀ aryl), wherein the C₆₋₁₀aryl is optionally substituted with one or more substituents eachindependently selected from the group consisting of halogen, hydroxy,—NO₂, and C₁₋₆alkoxy, and wherein the C₁₋₃ alkylene is optionallysubstituted with one or more substituents each independently selectedfrom the group consisting of C₆₋₁₀ aryl.

In some embodiments, R³ is —C₁₋₃ alkylene(C₆₋₁₀ aryl), wherein the C₆₋₁₀aryl is optionally substituted with one or more substituents eachindependently selected from the group consisting of halogen, hydroxy,—NO₂, and C₁₋₆alkoxy.

In some embodiments, R³ is selected from the group consisting of —C₁₋₂alkylene(C₆₋₁₀ aryl) and —C₁₋₂ alkylene(5- to 10-membered heteroaryl),wherein the C₆₋₁₀ aryl and the 5- to 10-membered heteroaryl areoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, hydroxy, —NO₂, andC₁₋₆alkoxy, and wherein the C₁₋₂ alkylene of —C₁₋₂ alkylene(C₆₋₁₀ aryl)and —C₁₋₂ alkylene(5- to 10-membered heteroaryl) is optionallysubstituted with one or more substituents each independently selectedfrom the group consisting of halogen, hydroxy, —NO₂, C₁₋₆alkoxy, andC₆₋₁₀ aryl.

In other embodiments, R³ is —C₁₋₂ alkylene(C₆₋₁₀ aryl), wherein theC₆₋₁₀ aryl is optionally substituted with one or more substituents eachindependently selected from the group consisting of halogen, hydroxy,—NO₂, and C₁₋₆alkoxy, and wherein the C₁₋₂ alkylene is optionallysubstituted with one or more substituents each independently selectedfrom the group consisting of halogen, hydroxy, —NO₂, C₁₋₆ alkoxy, andC₆₋₁₀ aryl.

In some embodiments, R³ is —C₁₋₂ alkylene(C₆₋₁₀ aryl), wherein the C₆₋₁₀aryl is optionally substituted with one or more substituents eachindependently selected from the group consisting of halogen, hydroxyl,—NO₂, and C₁₋₆ alkoxy. In some embodiments, R³ is —C₁₋₂ alkylene(C₆₋₁₀aryl), wherein the C₆₋₁₀ aryl is optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen, hydroxy and —NO₂. In some embodiments, R³ is —C₁₋₂alkylene(C₆₋₁₀ aryl), wherein the C₆₋₁₀ aryl is optionally substitutedwith one or more substituents each independently selected from the groupconsisting of halogen and hydroxy. In some embodiments, R³ is —C₁₋₂alkylene(C₆₋₁₀ aryl), wherein the C₆₋₁₀ aryl is optionally substitutedwith hydroxy.

In some embodiments, R³ is —CH₂-phenyl or —CH₂-naphthyl, wherein phenylor naphthyl may be optionally substituted with 1 or 2 substituents eachindependently selected from the group consisting of halogen, hydroxy,—NO₂, and C₁₋₆ alkoxy. In other embodiments, R³ is —CH₂-phenyl or—CH₂-naphthyl, wherein the phenyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen, hydroxyl, and —NO₂. In some embodiments, R³ is —CH₂-phenylor —CH₂-naphthyl, wherein the phenyl is optionally substituted with oneor more substituents each independently selected from the groupconsisting of halogen and hydroxyl. In some embodiments, R³ is—CH₂-phenyl or —CH₂-naphthyl, wherein the phenyl is optionallysubstituted with hydroxyl.

In some embodiments, R³ is —CH₂-phenyl, wherein phenyl may be optionallysubstituted with 1 or 2 substituents each independently selected fromthe group consisting of halogen, hydroxy, —NO₂, and C₁₋₆alkoxy. In someembodiments, R³ is —CH₂-phenyl, wherein phenyl may be optionallysubstituted with 1 or 2 substituents each independently selected fromthe group consisting of halogen, hydroxy, and —NO₂. In some embodiments,R³ is —CH₂-phenyl, wherein phenyl is unsubstituted. In some embodiments,R³ is —CH₂-phenyl, wherein phenyl is substituted with 1 or 2substituents each independently selected from the group consisting ofhalogen, hydroxy, —NO₂, and C₁₋₆alkoxy. In some embodiments, R³ is—CH₂-phenyl, wherein phenyl is substituted with 1 or 2 substituents eachindependently selected from the group consisting of halogen, hydroxy,and —NO₂. In some embodiments, R³ is —CH₂-phenyl, wherein phenyl issubstituted with 1 or 2 substituents each independently selected fromthe group consisting of halogen and hydroxy.

In some embodiments, R³ is —CH₂-phenyl, wherein phenyl is substitutedwith 1 or 2 substituents each independently selected from the groupconsisting of —F, —Cl, —Br, and —I. In some embodiments, R³ is—CH₂-phenyl, wherein phenyl is substituted with 1 or 2 substituents eachof which is —F. In some embodiments, R³ is —CH₂-phenyl, wherein phenylis substituted with 1 or 2 substituents each of which is —Cl. In someembodiments, R³ is —CH₂-phenyl, wherein phenyl is substituted with 1 or2 substituents each of which is —Br. In some embodiments, R³ is—CH₂-phenyl, wherein phenyl is substituted with 1 or 2 substituents eachof which is —I. In some embodiments, R³ is —CH₂-phenyl, wherein phenylis substituted with 1 substituent which is —F. In some embodiments, R³is —CH₂-phenyl, wherein phenyl is substituted with 1 substituent whichis —Cl. In some embodiments, R³ is —CH₂-phenyl, wherein phenyl issubstituted with 1 substituent which is —Br. In some embodiments, R³ is—CH₂-phenyl, wherein phenyl is substituted with 1 substituent which is—I.

In some embodiments, R³ is —CH₂-phenyl, wherein phenyl is substitutedwith 1 or 2 substituents each of which is hydroxy. In some embodiments,R³ is —CH₂-phenyl, wherein phenyl is substituted with 1 substituentwhich is hydroxy. In some embodiments, R³ is —CH₂-phenyl, wherein phenylis substituted with 1 or 2 substituents each of which is —NO₂. In someembodiments, R³ is —CH₂-phenyl, wherein phenyl is substituted with 1substituent which is —NO₂. In some embodiments, R³ is —CH₂-phenyl,wherein phenyl is substituted with 1 or 2 substituents each of which isindependently C₁₋₆alkoxy. In some embodiments, R³ is —CH₂-phenyl,wherein phenyl is substituted with 1 or 2 substituents each of which isindependently C₁₋₃ alkoxy. In some embodiments, R³ is —CH₂-phenyl,wherein phenyl is substituted with 1 substituent which is methoxy.

In some embodiments, R³ is

wherein R⁸⁹ is H, halogen, hydroxyl or C₁₋₃ alkoxy. In some embodiments,R⁸⁹ is H, halogen or hydroxyl. In some embodiments, R⁸⁹ is H, Cl orhydroxyl. In some embodiments, R⁸⁹ is Cl or hydroxyl. In someembodiments, R⁸⁹ is hydroxyl.

In some embodiments, R³ is —C₁₋₂ alkylene(C₁₀ aryl), wherein the C₁₀aryl is optionally substituted with one or more substituents eachindependently selected from the group consisting of halogen, hydroxyland —NO₂, and C₁₋₆ alkoxy. In some embodiments, R³ is —CH₂-naphthyl.

In some embodiments, R³ is —C₁₋₂ alkylene(6-membered heteroaryl),wherein the 6-membered heteroaryl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen, hydroxy, —NO₂, and C₁₋₆alkoxy.

In some embodiments, R³ is selected from the group consisting of—CH₂-pyridinyl, —CH₂— indolyl, —CH₂-thiophenyl, —CH₂-thiazolyl,—CH₂-furanyl, —CH₂-benzothiophenyl, and —CH₂— imidazolyl. In someembodiments, R³ is —CH₂-pyridinyl. In some embodiments, R³ is—CH₂-indolyl. In some embodiments, R³ is —CH₂-thiophenyl. In someembodiments, R³ is —CH₂-thiazolyl. In some embodiments, R³ is—CH₂-furanyl. In some embodiments, R³ is —CH₂-benzothiophenyl. In someembodiments, R³ is —CH₂-imidazolyl.

In some embodiments, R³ is selected from the group consisting of —C₁₋₂alkylene(C₆ aryl) and —C₁₋₂ alkylene(6-membered heteroaryl), wherein theC₆ aryl and the 6-membered heteroaryl are optionally substituted withhydroxyl. In other embodiments, R³ is —CH₂-phenyl or —CH₂-pyridinyl,wherein the phenyl is optionally substituted with hydroxyl.

Embodiments of R⁴

In some embodiments, R⁴ is selected from the group consisting of:

-   -   (i) —C₁₋₆ alkylene-N(R³)C(O)NR⁵¹R⁵², wherein each of R⁵¹ and R⁵²        is independently selected from the group consisting of H,        C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein        the C₁₋₆alkyl is optionally substituted with one or more        substituents, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents, and wherein R⁵³ is H or C₁₋₆ alkyl;    -   (ii) —C₁₋₆ alkylene-N(R⁵⁵)C(O)R⁵⁴, wherein R⁵⁴ is selected from        the group consisting of C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, wherein the C₁₋₆ alkyl is optionally        substituted with one or more substituents, and wherein the C₆₋₁₀        aryl and 5- to 10-membered heteroaryl are optionally substituted        with one or more substituents, and wherein R⁵⁵ is H or C₁₋₆        alkyl;    -   (iii) —(C₆₋₁₀ arylene)-C(O)NR⁵⁶R⁵⁷ or —C₁₋₆ alkylene-(C₆₋₁₀        arylene)-C(O)NR⁵⁶R⁵⁷, wherein each of R⁵⁶ and R⁵⁷ is        independently selected from the group consisting of H, C₁₋₆        alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the        C₁₋₆ alkyl is optionally substituted with one or more        substituents, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents;    -   (iv) —(C₆₋₁₀ arylene)-N(R⁵⁹)C(O)R⁵⁸ or —C₁₋₆ alkylene-(C₆₋₁₀        arylene)-N(R⁵⁹)C(O)R⁵⁸, wherein R⁵⁸ is selected from the group        consisting of C₁₋₆ alkyl, C₆₋₁₀ aryl, 5- to 10-membered        heteroaryl, and 5- to 10-membered heterocycloalkyl, wherein the        C₁₋₆alkyl is optionally substituted with one or more        substituents, and wherein the C₆₋₁₀ aryl, 5- to 10-membered        heteroaryl, and 5- to 10-membered heterocycloalkyl are        optionally substituted with one or more substituents, and        wherein R⁵⁹ is H or C₁₋₆ alkyl;    -   (v) —(C₆₋₁₀ arylene)-N(R⁶²)C(O)NR⁶⁰R⁶¹ or —C₁₋₆ alkylene-(C₆₋₁₀        arylene)-N(R⁶²)C(O)NR⁶⁰R⁶¹, wherein each of R⁶⁰ and R⁶¹ is        independently selected from the group consisting of H, C₁₋₆        alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the        C₁₋₆ alkyl is optionally substituted with one or more        substituents, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents, and wherein R⁶² is H or C₁₋₆ alkyl;    -   (vi) —(C₆₋₁₀ arylene)-N(R⁶⁴)SO₂R⁶³ or —C₁₋₆ alkylene-(C₆₋₁₀        arylene)-N(R⁶⁴)SO₂R⁶³, wherein R⁶³ is selected from the group        consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-membered        heteroaryl, wherein the C₁₋₆alkyl is optionally substituted with        one or more substituents, and wherein the C₆₋₁₀ aryl and 5- to        10-membered heteroaryl are optionally substituted with one or        more substituents, and wherein R⁶⁴ is H or C₁₋₆ alkyl;    -   (vii) —(C₆₋₁₀ arylene)-SO₂NR⁶⁵R⁶⁶ or —C₁₋₆ alkylene-(C₆₋₁₀        arylene)-SO₂NR⁶⁵R⁶⁶, wherein each of R⁶⁵ and R⁶⁶ is        independently selected from the group consisting of H,        C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein        the C₁₋₆ alkyl is optionally substituted with one or more        substituents, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents;    -   (viii) —(C₆₋₁₀ arylene)-(C₁₋₆ alkylene)-NR⁶⁷R⁶⁸ or —C₁₋₆        alkylene-(C₆₋₁₀ arylene)-(C₁₋₆ alkylene)-NR⁶⁷R⁶⁸, wherein:        -   each of R⁶⁷ and R⁶⁸ is independently selected from the group            consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, 5- to 10-membered            heteroaryl, —C(O)R⁶⁹, and —C(O)NR⁷⁰R⁷¹, wherein the            C₁₋₆alkyl is optionally substituted with one or more            substituents, and wherein the C₆₋₁₀ aryl and 5- to            10-membered heteroaryl are optionally substituted with one            or more substituents;        -   R⁶⁹ is selected from the group consisting of C₁₋₆alkyl,            C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the            C₁₋₆alkyl is optionally substituted with one or more            substituents, and wherein the C₆₋₁₀ aryl and 5- to            10-membered heteroaryl are optionally substituted with one            or more substituents; and        -   each of R⁷⁰ and R⁷¹ is independently selected from the group            consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to            10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally            substituted with one or more substituents, and wherein the            C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally            substituted with one or more substituents;    -   (ix) —(C₆₋₁₀ arylene)-NR⁷²R⁷³ or —C₁₋₆ alkylene-(C₆₋₁₀        arylene)-NR⁷²R⁷³, wherein each of R⁷² and R⁷³ is independently        selected from the group consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl,        and 5- to 10-membered heteroaryl, wherein the C₁₋₆ alkyl is        optionally substituted with one or more substituents, and        wherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are        optionally substituted with one or more substituents;    -   (x) —(C₆₋₁₀ arylene)-OR⁷⁴ or —C₁₋₆ alkylene-(C₆₋₁₀        arylene)-OR⁷⁴, wherein R⁷⁴ is selected from the group consisting        of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5-to 10-membered heteroaryl,        wherein the C₁₋₆alkyl is optionally substituted with one or more        substituents, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents;    -   (xi) —C₁₋₆ alkylene-(C₆₋₁₀ arylene)-N(R⁷⁵)—C(O)—CHR⁷⁶—NR⁷⁷R⁷⁸,        wherein R⁷⁵ is H or CH₃, R⁷⁶ is H or C₁₋₆alkyl optionally        substituted with one or more substituents each independently        selected from the group consisting of hydroxyl, —COOH, —NH₂,        —C(O)NH₂, and —N(H)C(O)NH₂, and each of R⁷⁷ and R⁷⁸ is        independently H, CH₃ or acetyl; and    -   (xii) —C₁₋₆ alkylene-(C₆₋₁₀ arylene)-CN.

In some embodiments, R⁴ is selected from the group consisting of:

-   -   (i) —C₁₋₆ alkylene-N(R⁵³)C(O)NR⁵¹R⁵², wherein each of R⁵¹ and        R⁵² is independently selected from the group consisting of H,        C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein        the C₁₋₆alkyl is optionally substituted with one or more        substituents, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents, and wherein R⁵³ is H or C₁₋₆ alkyl;    -   (ii) —C₁₋₆ alkylene-N(R⁵⁵)C(O)R⁵⁴, wherein R⁵⁴ is selected from        the group consisting of C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, wherein the C₁₋₆ alkyl is optionally        substituted with one or more substituents, and wherein the C₆₋₁₀        aryl and 5- to 10-membered heteroaryl are optionally substituted        with one or more substituents, and wherein R⁵⁵ is H or C₁₋₆        alkyl;    -   (iii) —(C₆₋₁₀ arylene)-C(O)NR⁵⁶R⁵⁷ or —C₁₋₆ alkylene-(C₆₋₁₀        arylene)-C(O)NR⁵⁶R⁵⁷, wherein each of R⁵⁶ and R⁵⁷ is        independently selected from the group consisting of H,        C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein        the C₁₋₆ alkyl is optionally substituted with one or more        substituents, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents;    -   (iv) —(C₆₋₁₀ arylene)-N(R⁵⁹)C(O)R⁵⁸ or —C₁₋₆ alkylene-(C₆₋₁₀        arylene)-N(R⁵⁹)C(O)R⁵⁸, wherein R⁵⁸ is selected from the group        consisting of C₁₋₆ alkyl, C₆₋₁₀ aryl, 5- to 10-membered        heteroaryl, and 5- to 10-membered heterocycloalkyl, wherein the        C₁₋₆alkyl is optionally substituted with one or more        substituents, and wherein the C₆₋₁₀ aryl, 5- to 10-membered        heteroaryl, and 5- to 10-membered heterocycloalkyl are        optionally substituted with one or more substituents, and        wherein R⁵⁹ is H or C₁₋₆ alkyl;    -   (v) —(C₆₋₁₀ arylene)-N(R⁶²)C(O)NR⁶⁰R⁶¹ or —C₁₋₆ alkylene-(C₆₋₁₀        arylene)-N(R⁶²)C(O)NR⁶⁰R⁶¹, wherein R⁶⁰ is selected from the        group consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, and R⁶¹ is selected from the group        consisting of C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-membered        heteroaryl, wherein the C₁₋₆alkyl of R⁶⁰ or R⁶¹ is optionally        substituted with one or more substituents, and wherein the C₆₋₁₀        aryl and 5- to 10-membered heteroaryl of R⁶⁰ or R⁶¹ are        optionally substituted with one or more substituents, and        wherein R⁶² is H or C₁₋₆ alkyl;    -   (vi) —(C₆₋₁₀ arylene)-N(R⁶⁴)SO₂R⁶³ or —C₁₋₆ alkylene-(C₆₋₁₀        arylene)-N(R⁶⁴)SO₂R⁶³, wherein R⁶³ is selected from the group        consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and 5-to 10-membered        heteroaryl, wherein the C₁₋₆alkyl is optionally substituted with        one or more substituents, and wherein the C₆₋₁₀ aryl and 5- to        10-membered heteroaryl are optionally substituted with one or        more substituents, and wherein R⁶⁴ is H or C₁₋₆ alkyl;    -   (vii) —(C₆₋₁₀ arylene)-SO₂NR⁶⁵R⁶⁶ or —C₁₋₆ alkylene-(C₆₋₁₀        arylene)-SO₂NR⁶⁵R⁶⁶, wherein each of R⁶⁵ and R⁶⁶ is        independently selected from the group consisting of H,        C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein        the C₁₋₆ alkyl is optionally substituted with one or more        substituents, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents;    -   (viii) —(C₆₋₁₀ arylene)-(C₁₋₆ alkylene)-NR⁶⁷R⁶⁸ or —C₁₋₆        alkylene-(C₆₋₁₀ arylene)-(C₁₋₆ alkylene)-NR⁶⁷R⁶⁸, wherein:        -   each of R⁶⁷ and R⁶⁸ is independently selected from the group            consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, 5- to 10-membered            heteroaryl, —C(O)R⁶⁹, and —C(O)NR⁷⁰R⁷¹, wherein the            C₁₋₆alkyl is optionally substituted with one or more            substituents, and wherein the C₆₋₁₀ aryl and 5- to            10-membered heteroaryl are optionally substituted with one            or more substituents;        -   R⁶⁹ is selected from the group consisting of C₁₋₆alkyl,            C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the            C₁₋₆alkyl is optionally substituted with one or more            substituents, and wherein the C₆₋₁₀ aryl and 5- to            10-membered heteroaryl are optionally substituted with one            or more substituents; and        -   each of R⁷⁰ and R⁷¹ is independently selected from the group            consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to            10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally            substituted with one or more substituents, and wherein the            C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally            substituted with one or more substituents;    -   (ix) —(C₆₋₁₀ arylene)-NR⁷²R⁷³ or —C₁₋₆ alkylene-(C₆₋₁₀        arylene)-NR⁷²R⁷³, wherein each of R⁷² and R⁷³ is independently        selected from the group consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl,        and 5- to 10-membered heteroaryl, wherein the C₁₋₆ alkyl is        optionally substituted with one or more substituents, and        wherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are        optionally substituted with one or more substituents;    -   (x) —(C₆₋₁₀ arylene)-OR⁷⁴ or —C₁₋₆ alkylene-(C₆₋₁₀        arylene)-OR⁷⁴, wherein R⁷⁴ is selected from the group consisting        of C₂₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl,        wherein the C₂₋₆alkyl is optionally substituted with one or more        substituents, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents;    -   (xi) —C₁₋₆ alkylene-(C₆₋₁₀ arylene)-N(R⁷⁵)—C(O)—CHR⁷⁶—NR⁷⁷R⁷⁸,        wherein R⁷⁵ is H or CH₃, R⁷⁶ is H or C₁₋₆alkyl optionally        substituted with one or more substituents each independently        selected from the group consisting of hydroxyl, —COOH, —NH₂,        —C(O)NH₂, and —N(H)C(O)NH₂, and each of R⁷⁷ and R⁷⁸ is        independently H, CH₃ or acetyl; and    -   (xii) —C₁₋₆ alkylene-(C₆₋₁₀ arylene)-CN.

In other embodiments, R⁴ is selected from the group consisting of:

-   -   (i) —C₁₋₆ alkylene-N(H)C(O)NR⁵¹R⁵², wherein each of R⁵¹ and R⁵²        is independently selected from the group consisting of H,        C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein        the C₁₋₆alkyl is optionally substituted with one or more        substituents, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents;    -   (ii) —C₁₋₆ alkylene-N(H)C(O)R⁵⁴, wherein R⁵⁴ is selected from        the group consisting of C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally        substituted with one or more substituents, and wherein the C₆₋₁₀        aryl and 5- to 10-membered heteroaryl are optionally substituted        with one or more substituents;    -   (iii) —(C₆₋₁₀ arylene)-C(O)NR⁵⁶R⁵⁷ or —C₁₋₆ alkylene-(C₆₋₁₀        arylene)-C(O)NR⁵⁶R⁵⁷, wherein each of R⁵⁶ and R⁵⁷ is        independently selected from the group consisting of H, C₁₋₆        alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the        C₁₋₆ alkyl is optionally substituted with one or more        substituents, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents;    -   (iv) —(C₆₋₁₀ arylene)-N(H)C(O)R⁵⁸ or —C₁₋₆ alkylene-(C₆₋₁₀        arylene)-N(H)C(O)R⁵⁸, wherein R⁵⁸ is selected from the group        consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, 5- to 10-membered        heteroaryl, and 5- to 10-membered heterocycloalkyl, wherein the        C₁₋₆alkyl is optionally substituted with one or more        substituents, and wherein the C₆₋₁₀ aryl, 5- to 10-membered        heteroaryl, and 5- to 10-membered heterocycloalkyl are        optionally substituted with one or more substituents;    -   (v) —(C₆₋₁₀ arylene)-N(H)C(O)NR⁶⁰R⁶¹ or —C₁₋₆ alkylene-(C₆₋₁₀        arylene)-N(H)C(O)NR⁶⁰R⁶¹, wherein each of R⁶⁰ and R⁶¹ is        independently selected from the group consisting of H, C₁₋₆        alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the        C₁₋₆alkyl is optionally substituted with one or more        substituents, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents;    -   (vi) —(C₆₋₁₀ arylene)-N(H)SO₂R⁶³ or —C₁₋₆ alkylene-(C₆₋₁₀        arylene)-N(H)SO₂R⁶³, wherein R⁶³ is selected from the group        consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-membered        heteroaryl, wherein the C₁₋₆alkyl is optionally substituted with        one or more substituents, and wherein the C₆₋₁₀ aryl and 5- to        10-membered heteroaryl are optionally substituted with one or        more substituents;    -   (vii) —(C₆₋₁₀ arylene)-SO₂NR⁶⁵R⁶⁶ or —C₁₋₆ alkylene-(C₆₋₁₀        arylene)-SO₂NR⁶⁵R⁶⁶, wherein each of R⁶⁵ and R⁶⁶ is selected        from the group consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5-        to 10-membered heteroaryl, wherein the C₁₋₆ alkyl is optionally        substituted with one or more substituents, and wherein the C₆₋₁₀        aryl and 5- to 10-membered heteroaryl are optionally substituted        with one or more substituents;    -   (viii) —(C₆₋₁₀ arylene)-(C₁₋₆ alkylene)-NR⁶⁷R⁶⁸ or —C₁₋₆        alkylene-(C₆₋₁₀ arylene)-(C₁₋₆ alkylene)-NR⁶⁷R⁶⁸, wherein:        -   each of R⁶⁷ and R⁶⁸ is independently selected from the group            consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, 5- to 10-membered            heteroaryl, —C(O)R⁶⁹, and —C(O)NR⁷⁰R⁷¹, wherein the            C₁₋₆alkyl is optionally substituted with one or more            substituents, and wherein the C₆₋₁₀ aryl and 5- to            10-membered heteroaryl are optionally substituted with one            or more substituents;        -   R⁶⁹ is selected from the group consisting of C₁₋₆alkyl,            C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the            C₁₋₆alkyl is optionally substituted with one or more            substituents, and wherein the C₆₋₁₀ aryl and 5- to            10-membered heteroaryl are optionally substituted with one            or more substituents; and        -   each of R⁷⁰ and R⁷¹ is independently selected from the group            consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to            10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally            substituted with one or more substituents, and wherein the            C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally            substituted with one or more substituents;    -   (ix) —(C₆₋₁₀ arylene)-NR⁷²R⁷³ or —C₁₋₆ alkylene-(C₆₋₁₀        arylene)-NR⁷²R⁷³, wherein each of R⁷² and R⁷³ is independently        selected from the group consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl,        and 5- to 10-membered heteroaryl, wherein the C₁₋₆ alkyl is        optionally substituted with one or more substituents, and        wherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are        optionally substituted with one or more substituents;    -   (x) —(C₆₋₁₀ arylene)-OR⁷⁴ or —C₁₋₆ alkylene-(C₆₋₁₀        arylene)-OR⁷⁴, wherein R⁷⁴ is selected from the group consisting        of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5-to 10-membered heteroaryl,        wherein the C₁₋₆alkyl is optionally substituted with one or more        substituents, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents;    -   (xi) —C₁₋₆ alkylene-(C₆₋₁₀ arylene)-N(R⁷⁵)—C(O)—CHR⁷⁶—N(H)R⁷⁸,        wherein R⁷⁵ is H or CH₃, R⁷⁶ is H or C₁₋₆alkyl optionally        substituted with one or more substituents each independently        selected from the group consisting of hydroxyl, —COOH, —NH₂,        —C(O)NH₂, and —N(H)C(O)NH₂, and R⁷⁸ is H, CH₃ or acetyl; and    -   (xii) —C₁₋₆ alkylene-(C₆₋₁₀ arylene)-CN.

In some embodiments, R⁴ is —C₁₋₆ alkylene-N(R⁵³)C(O)NR⁵¹R⁵², whereineach of R⁵¹ and R⁵² is independently selected from the group consistingof H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, whereinthe C₁₋₆alkyl is optionally substituted with one or more substituents,and wherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl areoptionally substituted with one or more substituents, and wherein R⁵³ isH or alkyl.

In other embodiments, R⁴ is —C₁₋₆ alkylene-N(R⁵³)C(O)NR⁵¹R⁵², whereineach of R⁵¹ and R⁵² is independently selected from the group consistingof H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, whereinthe C₁₋₆alkyl is optionally substituted with one or more substituentseach independently selected from the group consisting of halogen, —OH,—NO₂, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆alkyl)₂, —C₁₋₆ alkyl, haloC₁₋₆ alkyl, aminoC₁₋₆ alkyl, C₆₋₁₀ aryl, 5- to10-membered heteroaryl, 5- to 10-membered heterocycloalkyl, C₅₋₁₀cycloalkyl, azido, —CN, —COR²⁰⁰ wherein R²⁰⁰ is C₁₋₆ alkyl or C₆₋₁₀aryl, —CO₂R²⁰¹ wherein R²⁰¹ is H or C₁₋₆ alkyl, —CONR²⁰²R²⁰³ whereinR²⁰² and R²⁰³ is H or C₁₋₆ alkyl, —NR²⁰⁴COR²⁰⁵ wherein R²⁰⁴ is H or C₁₋₆alkyl and R²⁰⁵ is C₁₋₆ alkyl, —SO₂NR²⁰⁶R²⁰⁷ wherein R²⁰⁶ and R²⁰⁷ is Hor C₁₋₆ alkyl, and —NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸ is H or C₁₋₆ alkyl andR²⁰⁹ is C₁₋₆ alkyl, and wherein the C₆₋₁₀ aryl and 5- to 10-memberedheteroaryl are optionally substituted with one or more substituents eachindependently selected from the group consisting of halogen, —OH, —NO₂,C₁₋₆alkoxy, C₁₋₆ haloalkoxy, —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)₂,—C₁₋₆ alkyl, haloC₁₋₆ alkyl, aminoC₁₋₆ alkyl, C₆₋₁₀ aryl, 5- to10-membered heteroaryl, 5- to 10-membered heterocycloalkyl, C₅₋₁₀cycloalkyl, azido, —CN, —COR²⁰⁰ wherein R²⁰⁰ is C₁₋₆ alkyl or C₆₋₁₀aryl, —CO₂R²⁰¹ wherein R²⁰¹ is H or C₁₋₆ alkyl, —CONR²⁰²R²⁰³ whereinR²⁰² and R²⁰³ is H or C₁₋₆ alkyl, —NR²⁰⁴COR²⁰⁵ wherein R²⁰⁴ is H or C₁₋₆alkyl and R²⁰⁵ is C₁₋₆ alkyl, —SO₂NR²⁰⁶R²⁰⁷ wherein R²⁰⁶ and R²⁰⁷ is Hor C₁₋₆ alkyl, and —NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸ is H or C₁₋₆ alkyl andR²⁰⁹ is C₁₋₆ alkyl, and wherein R⁵³ is H or C₁₋₆alkyl.

In some embodiments, R⁴ is —C₁₋₆ alkylene-N(H)C(O)NR⁵¹R⁵², wherein eachof R⁵¹ and R⁵² is independently selected from the group consisting of H,C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein theC₁₋₆alkyl is optionally substituted with one or more substituents, andwherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionallysubstituted with one or more substituents.

In other embodiments, R⁴ is —C₁₋₆ alkylene-N(H)C(O)NR⁵¹R⁵², wherein eachof R⁵¹ and R⁵² is independently selected from the group consisting of H,C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein theC₁₋₆alkyl is optionally substituted with one or more substituents eachindependently selected from the group consisting of halogen, —OH, —NO₂,C₁₋₆alkoxy, C₁₋₆ haloalkoxy, —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)₂,—C₁₋₆ alkyl, haloC₁₋₆ alkyl, aminoC₁₋₆ alkyl, C₆₋₁₀ aryl, 5- to10-membered heteroaryl, 5- to 10-membered heterocycloalkyl, C₅₋₁₀cycloalkyl, azido, —CN, —COR²⁰⁰ wherein R²⁰⁰ is C₁₋₆ alkyl or C₆₋₁₀aryl, —CO₂R²⁰¹ wherein R²⁰¹ is H or C₁₋₆ alkyl, —CONR²⁰²R²⁰³ whereinR²⁰² and R²⁰³ is H or C₁₋₆ alkyl, —NR²⁰⁴COR²⁰⁵ wherein R²⁰⁴ is H or C₁₋₆alkyl and R²⁰⁵ is C₁₋₆ alkyl, —SO₂NR²⁰⁶R²⁰⁷ wherein R²⁰⁶ and R²⁰⁷ is Hor C₁₋₆ alkyl, and —NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸ is H or C₁₋₆ alkyl andR²⁰⁹ is C₁₋₆ alkyl, and wherein the C₆₋₁₀ aryl and 5- to 10-memberedheteroaryl are optionally substituted with one or more substituents eachindependently selected from the group consisting of halogen, —OH, —NO₂,C₁₋₆alkoxy, C₁₋₆ haloalkoxy, —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)₂,—C₁₋₆ alkyl, haloC₁₋₆ alkyl, aminoC₁₋₆ alkyl, C₆₋₁₀ aryl, 5- to10-membered heteroaryl, 5- to 10-membered heterocycloalkyl, C₅₋₁₀cycloalkyl, azido, —CN, —COR²⁰⁰ wherein R²⁰⁰ is C₁₋₆ alkyl or C₆₋₁₀aryl, —CO₂R²⁰¹ wherein R²⁰¹ is H or C₁₋₆ alkyl, —CONR²⁰²R²⁰³ whereinR²⁰² and R²⁰³ is H or C₁₋₆ alkyl, —NR²⁰⁴COR²⁰⁵ wherein R²⁰⁴ is H or C₁₋₆alkyl and R²⁰⁵ is C₁₋₆ alkyl, —SO₂NR²⁰⁶R²⁰⁷ wherein R²⁰⁶ and R²⁰⁷ is Hor C₁₋₆ alkyl, and —NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸ is H or C₁₋₆ alkyl andR²⁰⁹ is C₁₋₆ alkyl. In some embodiments, R⁴ is —C₃₋₄alkylene-N(H)C(O)NR⁵¹R⁵² and each of R⁵¹ and R⁵² is H.

In some embodiments, R⁴ is:

wherein each of R⁹⁰ and R⁹¹ is independently selected from the groupconsisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl, wherein the C₁₋₆alkyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl and 5-to 10-membered heteroaryl are optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein n² is 1, 2, 3 or 4. Insome embodiments, each of R⁹⁰ and R⁹¹ is H. In some embodiments, n² is 3or 4. In some embodiments, n² is 3. In other embodiments, n² is 4.

In some embodiments, R⁴ is

wherein each of R⁹² and R⁹³ is independently selected from the groupconsisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 6- to 10-memberedheteroaryl, wherein the C₁₋₆alkyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl and 6-to 10-membered heteroaryl are optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen, —OH, —NO₂, and C₁₋₆alkoxy. In some embodiments, each of R⁹² andR⁹³ is H.

In some embodiments, R⁴ is

wherein each of R⁹⁴ and R⁹⁵ is independently selected from the groupconsisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 6- to 10-memberedheteroaryl, wherein the C₁₋₆alkyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl and 6-to 10-membered heteroaryl are optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen, —OH, —NO₂, and C₁₋₆alkoxy. In other embodiments, each of R⁹⁴and R⁹⁵ is H.

In some embodiments, R⁴ is —C₁₋₆ alkylene-N(R⁵⁵)C(O)R⁵⁴, wherein R⁵⁴ isselected from the group consisting of C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to10-membered heteroaryl, wherein the C₁₋₆ alkyl is optionally substitutedwith one or more substituents, and wherein the C₆₋₁₀ aryl and 5- to10-membered heteroaryl are optionally substituted with one or moresubstituents, and wherein R⁵⁵ is H or C₁₋₆alkyl.

In other embodiments, R⁴ is —C₁₋₆ alkylene-N(R⁵⁵)C(O)R⁵⁴, wherein R⁵⁴ isselected from the group consisting of C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to10-membered heteroaryl, wherein the C₁₋₆ alkyl is optionally substitutedwith one or more substituents each independently selected from the groupconsisting of halogen, —OH, —NO₂, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, —NH₂,—NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)₂, —C₁₋₆ alkyl, haloC₁₋₆ alkyl, aminoC₁₋₆alkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, 5- to 10-memberedheterocycloalkyl, C₅₋₁₀ cycloalkyl, azido, —CN, —COR²⁰⁰ wherein R²⁰⁰ isC₁₋₆ alkyl or C₆₋₁₀ aryl, —CO₂R²⁰¹ wherein R²⁰¹ is H or C₁₋₆ alkyl,—CONR²⁰²R²⁰³ wherein R²⁰² and R²⁰³ is H or C₁₋₆ alkyl, —NR²⁰⁴COR²⁰⁵wherein R²⁰⁴ is H or C₁₋₆ alkyl and R²⁰⁵ is C₁₋₆ alkyl, —SO₂NR²⁰⁶R²⁰⁷wherein R²⁰⁶ and R²⁰⁷ is H or C₁₋₆ alkyl, and —NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸is H or C₁₋₆ alkyl and R²⁰⁹ is C₁₋₆ alkyl, and wherein the C₆₋₁₀ aryland 5- to 10-membered heteroaryl are optionally substituted with one ormore substituents each independently selected from the group consistingof halogen, —OH, —NO₂, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, —NH₂, —NH(C₁₋₆alkyl), —N(C₁₋₆ alkyl)₂, —C₁₋₆ alkyl, haloC₁₋₆ alkyl, aminoC₁₋₆ alkyl,C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, 5- to 10-memberedheterocycloalkyl, C₅₋₁₀ cycloalkyl, azido, —CN, —COR²⁰⁰ wherein R²⁰⁰ isC₁₋₆ alkyl or C₆₋₁₀ aryl, —CO₂R²⁰¹ wherein R²⁰¹ is H or C₁₋₆ alkyl,—CONR²⁰²R²⁰³ wherein R²⁰² and R²⁰³ is H or C₁₋₆ alkyl, —NR²⁰⁴COR²⁰⁵wherein R²⁰⁴ is H or C₁₋₆ alkyl and R²⁰⁵ is C₁₋₆ alkyl, —SO₂NR²⁰⁶R²⁰⁷wherein R²⁰⁶ and R²⁰⁷ is H or C₁₋₆ alkyl, and —NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸is H or C₁₋₆ alkyl and R²⁰⁹ is C₁₋₆ alkyl, and wherein R⁵⁵ is H orC₁₋₆alkyl.

In some embodiments, R⁴ is —C₁₋₆ alkylene-NHC(O)R⁵⁴, wherein R⁵⁴ isselected from the group consisting of C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to10-membered heteroaryl, wherein the C₁₋₆ alkyl is optionally substitutedwith one or more substituents, and wherein the C₆₋₁₀ aryl and 5- to10-membered heteroaryl are optionally substituted with one or moresubstituents.

In other embodiments, R⁴ is —C₁₋₆ alkylene-NHC(O)R⁵⁴, wherein R⁵⁴ isselected from the group consisting of C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to10-membered heteroaryl, wherein the C₁₋₆ alkyl is optionally substitutedwith one or more substituents each independently selected from the groupconsisting of halogen, —OH, —NO₂, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, —NH₂,—NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)₂, —C₁₋₆ alkyl, haloC₁₋₆ alkyl, aminoC₁₋₆alkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, 5- to 10-memberedheterocycloalkyl, C₅₋₁₀ cycloalkyl, azido, —CN, —COR²⁰⁰ wherein R²⁰⁰ isC₁₋₆ alkyl or C₆₋₁₀ aryl, —CO₂R²⁰¹ wherein R²⁰¹ is H or C₁₋₆ alkyl,—CONR²⁰²R²⁰³ wherein R²⁰² and R²⁰³ is H or C₁₋₆ alkyl, —NR²⁰⁴COR²⁰⁵wherein R²⁰⁴ is H or C₁₋₆ alkyl and R²⁰⁵ is C₁₋₆ alkyl, —SO₂NR²⁰⁶R²⁰⁷wherein R²⁰⁶ and R²⁰⁷ is H or C₁₋₆ alkyl, and —NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸is H or C₁₋₆ alkyl and R²⁰⁹ is C₁₋₆ alkyl, and wherein the C₆₋₁₀ aryland 5- to 10-membered heteroaryl are optionally substituted with one ormore substituents each independently selected from the group consistingof halogen, —OH, —NO₂, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, —NH₂, —NH(C₁₋₆alkyl), —N(C₁₋₆ alkyl)₂, —C₁₋₆ alkyl, haloC₁₋₆ alkyl, aminoC₁₋₆ alkyl,C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, 5- to 10-memberedheterocycloalkyl, C₅₋₁₀ cycloalkyl, azido, —CN, —COR²⁰⁰ wherein R²⁰⁰ isC₁₋₆ alkyl or C₆₋₁₀ aryl, —CO₂R²⁰¹ wherein R²⁰¹ is H or C₁₋₆ alkyl,—CONR²⁰²R²⁰³ wherein R²⁰² and R²⁰³ is H or C₁₋₆ alkyl, —NR²⁰⁴COR²⁰⁵wherein R²⁰⁴ is H or C₁₋₆ alkyl and R²⁰⁵ is C₁₋₆ alkyl, —SO₂NR²⁰⁶R²⁰⁷wherein R²⁰⁶ and R²⁰⁷ is H or C₁₋₆ alkyl, and —NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸is H or C₁₋₆ alkyl and R²⁰⁹ is C₁₋₆ alkyl.

In some embodiments, R⁴ is —C₃₋₄ alkylene-NHC(O)R⁵⁴ and R⁵⁴ is 5- to10-membered heteroaryl optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen, hydroxy, —NO₂, and C₁₋₆alkoxy.

In other embodiments, R⁴ is —C₃₋₄ alkylene-NHC(O)R⁵⁴ and R⁵⁴ ispyridinyl optionally substituted with one or more substituents eachindependently selected from the group consisting of halogen, hydroxy,—NO₂, and C₁₋₆alkoxy.

In some embodiments, R⁴ is:

wherein R⁹⁶ is selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀aryl, and 5- to 10-membered heteroaryl, wherein the C₁₋₆ alkyl isoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, —OH, —NO₂, andC₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl and 5- to 10-membered heteroarylare optionally substituted with one or more substituents eachindependently selected from the group consisting of halogen, —OH, —NO₂,and C₁₋₆alkoxy, and wherein n³ is 1, 2, 3, or 4. In some embodiments,R⁹⁶ is pyridinyl. In some embodiments, n³ is 3 or 4. In someembodiments, n³ is 3. In other embodiments, n³ is 4.

In some embodiments, R⁴ is

wherein R⁹⁷ is selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀aryl, and 5- to 10-membered heteroaryl, wherein the C₁₋₆ alkyl isoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, —OH, —NO₂, andC₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl and 5- to 10-membered heteroarylare optionally substituted with one or more substituents eachindependently selected from the group consisting of halogen, —OH, —NO₂,and C₁₋₆alkoxy. In some embodiments, R⁹⁷ is C₆ aryl or 5- to 6-memberedheteroaryl.

In some embodiments, R⁴ is

wherein R⁹⁸ is selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀aryl, and 5- to 10-membered heteroaryl, wherein the C₁₋₆ alkyl isoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, —OH, —NO₂, andC₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl and 5- to 10-membered heteroarylare optionally substituted with one or more substituents eachindependently selected from the group consisting of halogen, —OH, —NO₂,and C₁₋₆alkoxy. In some embodiments, R⁹⁸ is C₆ aryl or 5- to 6-memberedheteroaryl.

In some embodiments, R⁴ is —(C₆₋₁₀ arylene)-C(O)NR⁵⁶R⁵⁷ or —C₁₋₆alkylene-(C₆₋₁₀ arylene)-C(O)NR⁵⁶R⁵⁷, wherein each of R⁵⁶ and R⁵⁷ isindependently selected from the group consisting of H, C₁₋₆alkyl, C₆₋₁₀aryl, and 5- to 10-membered heteroaryl, wherein the C₁₋₆ alkyl isoptionally substituted with one or more substituents, and wherein theC₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally substitutedwith one or more substituents.

In other embodiments, R⁴ is —(C₆₋₁₀ arylene)-C(O)NR⁵⁶R⁵⁷ or —C₁₋₆alkylene-(C₆₋₁₀ arylene)-C(O)NR⁵⁶R⁵⁷, wherein each of R⁵⁶ and R⁵⁷ isindependently selected from the group consisting of H, C₁₋₆alkyl, C₆₋₁₀aryl, and 5- to 10-membered heteroaryl, wherein the C₁₋₆alkyl isoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, —OH, —NO₂, C₁₋₆alkoxy,C₁₋₆ haloalkoxy, —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)₂, —C₁₋₆ alkyl,haloC₁₋₆ alkyl, aminoC₁₋₆ alkyl, C₆₋₁₀ aryl, 5- to 10-memberedheteroaryl, 5- to 10-membered heterocycloalkyl, C₅₋₁₀ cycloalkyl, azido,—CN, —COR²⁰⁰ wherein R²⁰⁰ is C₁₋₆ alkyl or C₆₋₁₀ aryl, —CO₂R²⁰¹ whereinR²⁰¹ is H or C₁₋₆ alkyl, —CONR²⁰²R²⁰³ wherein R²⁰² and R²⁰³ is H or C₁₋₆alkyl, —NR²⁰⁴COR²⁰⁵ wherein R²⁰⁴ is H or C₁₋₆ alkyl and R²⁰⁵ is C₁₋₆alkyl, —SO₂NR²⁰⁶R²⁰⁷ wherein R²⁰⁶ and R²⁰⁷ is H or C₁₋₆ alkyl, and—NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸ is H or C₁₋₆ alkyl and R²⁰⁹ is C₁₋₆ alkyl,and wherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl areoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, —OH, —NO₂, C₁₋₆alkoxy,C₁₋₆ haloalkoxy, —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)₂, —C₁₋₆ alkyl,haloC₁₋₆ alkyl, aminoC₁₋₆ alkyl, C₆₋₁₀ aryl, 5- to 10-memberedheteroaryl, 5- to 10-membered heterocycloalkyl, C₅₋₁₀ cycloalkyl, azido,—CN, —COR²⁰⁰ wherein R²⁰⁰ is C₁₋₆ alkyl or C₆₋₁₀ aryl, —CO₂R²⁰¹ whereinR²⁰¹ is H or C₁₋₆ alkyl, —CONR²⁰²R²⁰³ wherein R²⁰² and R²⁰³ is H or C₁₋₆alkyl, —NR²⁰⁴COR²⁰⁵ wherein R²⁰⁴ is H or C₁₋₆ alkyl and R²⁰⁵ is C₁₋₆alkyl, —SO₂NR²⁰⁶R²⁰⁷ wherein R²⁰⁶ and R²⁰⁷ is H or C₁₋₆ alkyl, and—NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸ is H or C₁₋₆ alkyl and R²⁰⁹ is C₁₋₆ alkyl. Insome embodiments, R⁴ is —C₁₋₂ alkylene-(C₆ arylene)-C(O)NR⁵⁶R⁵⁷ and eachof R⁵⁶ and R⁵⁷ is H.

In some embodiments, R⁴ is:

wherein each of R⁹⁹ and R¹⁰⁰ is independently selected from the groupconsisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl, wherein the C₁₋₆alkyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl and 5-to 10-membered heteroaryl are optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein n⁴ is 0, 1, 2, 3, or 4.In other embodiments, each of R⁹⁹ and R¹⁰⁰ is independently selectedfrom the group consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to10-membered heteroaryl. In some embodiments, each of R⁹⁹ and R¹⁰⁰ isindependently selected from the group consisting of H and C₁₋₆alkyl. Insome embodiments, each of R⁹⁹ and R¹⁰⁰ is H. In some embodiments, n⁴ is1 or 2. In some embodiments, n⁴ is 1. In other embodiments, n⁴ is 2.

In some embodiments, R⁴ is:

wherein each of R¹⁰¹ and R¹⁰² is independently selected from the groupconsisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl, wherein the C₁₋₆alkyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl and 5-to 10-membered heteroaryl are optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen, —OH, —NO₂, and C₁₋₆alkoxy. In other embodiments, each of R¹⁰¹and R¹⁰² is independently selected from the group consisting of H,C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl. In someembodiments, each of R¹⁰¹ and R¹⁰² is independently selected from thegroup consisting of H and C₁₋₆ alkyl. In some embodiments, each of R¹⁰¹and R¹⁰² is H.

In some embodiments, R⁴ is —(C₆₋₁₀ arylene)-N(R⁵⁹)C(O)R⁵⁸ or —C₁₋₆alkylene-(C₆₋₁₀ arylene)-N(R⁵⁹)C(O)R⁵⁸, wherein R⁵⁸ is selected from thegroup consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl,and 5- to 10-membered heterocycloalkyl, wherein the C₁₋₆alkyl isoptionally substituted with one or more substituents, and wherein theC₆₋₁₀ aryl, 5- to 10-membered heteroaryl, and 5- to 10-memberedheterocycloalkyl are optionally substituted with one or moresubstituents, and wherein R⁵⁹ is H or C₁₋₆alkyl.

In some embodiments, R⁴ is —(C₆₋₁₀ arylene)-N(R⁵⁹)C(O)R⁵⁸ or —C₁₋₆alkylene-(C₆₋₁₀ arylene)-N(R⁵⁹)C(O)R⁵⁸, wherein R⁵⁸ is selected from thegroup consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl,and 5- to 10-membered heterocycloalkyl, wherein the C₁₋₆alkyl isoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, —OH, —NO₂, C₁₋₆alkoxy,C₁₋₆ haloalkoxy, —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)₂, —C₁₋₆ alkyl,haloC₁₋₆ alkyl, aminoC₁₋₆ alkyl, C₆₋₁₀ aryl, 5- to 10-memberedheteroaryl, 5- to 10-membered heterocycloalkyl, C₅₋₁₀ cycloalkyl, azido,—CN, —COR²⁰⁰ wherein R²⁰⁰ is C₁₋₆ alkyl or C₆₋₁₀ aryl, —CO₂R²⁰¹ whereinR²⁰¹ is H or C₁₋₆ alkyl, —CONR²⁰²R²⁰³ wherein R²⁰² and R²⁰³ is H or C₁₋₆alkyl, —NR²⁰⁴COR²⁰⁵ wherein R²⁰⁴ is H or C₁₋₆ alkyl and R²⁰⁵ is C₁₋₆alkyl, —SO₂NR²⁰⁶R²⁰⁷ wherein R²⁰⁶ and R²⁰⁷ is H or C₁₋₆ alkyl, and—NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸ is H or C₁₋₆ alkyl and R²⁰⁹ is C₁₋₆ alkyl,and wherein the C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, and 5- to10-membered heterocycloalkyl are optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen, —OH, —NO₂, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, —NH₂, —NH(C₁₋₆ alkyl),—N(C₁₋₆ alkyl)₂, —C₁₋₆ alkyl, haloC₁₋₆ alkyl, aminoC₁₋₆ alkyl, C₆₋₁₀aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocycloalkyl,C₅₋₁₀ cycloalkyl, azido, —CN, —COR²⁰⁰ wherein R²⁰⁰ is C₁₋₆ alkyl orC₆₋₁₀ aryl, —CO₂R²⁰¹ wherein R²⁰¹ is H or C₁₋₆ alkyl, —CONR²⁰²R²⁰³wherein R²⁰² and R²⁰³ is H or C₁₋₆ alkyl, —NR²⁰⁴COR²⁰⁵ wherein R²⁰⁴ is Hor C₁₋₆ alkyl and R²⁰⁵ is C₁₋₆ alkyl, —SO₂NR²⁰⁶R²⁰⁷ wherein R²⁰⁶ andR²⁰⁷ is H or C₁₋₆ alkyl, and —NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸ is H or C₁₋₆alkyl and R²⁰⁹ is C₁₋₆ alkyl, and wherein R⁵⁹ is H or C₁ 6alkyl.

In some embodiments, R⁴ is —(C₆₋₁₀ arylene)-N(H)C(O)R⁵⁸ or —C₁₋₆alkylene-(C₆₋₁₀ arylene)-N(H)C(O)R⁵⁸, wherein R⁵⁸ is selected from thegroup consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl,and 5- to 10-membered heterocycloalkyl, wherein the C₁₋₆alkyl isoptionally substituted with one or more substituents, and wherein theC₆₋₁₀ aryl, 5- to 10-membered heteroaryl, and 5- to 10-memberedheterocycloalkyl are optionally substituted with one or moresubstituents.

In some embodiments, R⁴ is —(C₆₋₁₀ arylene)-N(H)C(O)R⁵⁸ or —C₁₋₆alkylene-(C₆₋₁₀ arylene)-N(H)C(O)R⁵⁸, wherein R⁵⁸ is selected from thegroup consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl,and 5- to 10-membered heterocycloalkyl, wherein the C₁₋₆alkyl isoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, —OH, —NO₂, C₁₋₆alkoxy,C₁₋₆ haloalkoxy, —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)₂, —C₁₋₆ alkyl,haloC₁₋₆ alkyl, aminoC₁₋₆ alkyl, C₆₋₁₀ aryl, 5- to 10-memberedheteroaryl, 5- to 10-membered heterocycloalkyl, C₅₋₁₀ cycloalkyl, azido,—CN, —COR²⁰⁰ wherein R²⁰⁰ is C₁₋₆ alkyl or C₆₋₁₀ aryl, —CO₂R²⁰¹ whereinR²⁰¹ is H or C₁₋₆ alkyl, —CONR²⁰²R²⁰³ wherein R²⁰² and R²⁰³ is H or C₁₋₆alkyl, —NR²⁰⁴COR²⁰⁵ wherein R²⁰⁴ is H or C₁₋₆ alkyl and R²⁰⁵ is C₁₋₆alkyl, —SO₂NR²⁰⁶R²⁰⁷ wherein R²⁰⁶ and R²⁰⁷ is H or C₁₋₆ alkyl, and—NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸ is H or C₁₋₆ alkyl and R²⁰⁹ is C₁₋₆ alkyl,and wherein the C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, and 5- to10-membered heterocycloalkyl are optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen, —OH, —NO₂, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, —NH₂, —NH(C₁₋₆ alkyl),—N(C₁₋₆ alkyl)₂, —C₁₋₆ alkyl, haloC₁₋₆ alkyl, aminoC₁₋₆ alkyl, C₆₋₁₀aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocycloalkyl,C₅₋₁₀ cycloalkyl, azido, —CN, —COR²⁰⁰ wherein R²⁰⁰ is C₁₋₆ alkyl orC₆₋₁₀ aryl, —CO₂R²⁰¹ wherein R²⁰¹ is H or C₁₋₆ alkyl, —CONR²⁰²R²⁰³wherein R²⁰² and R²⁰³ is H or C₁₋₆ alkyl, —NR²⁰⁴COR²⁰⁵ wherein R²⁰⁴ is Hor C₁₋₆ alkyl and R²⁰ is C₁₋₆ alkyl, —SO₂NR²⁰⁶R²⁰⁷ wherein R²⁰⁶ and R²⁰⁷is H or C₁₋₆ alkyl, and —NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸ is H or C₁₋₆ alkyland R²⁰⁹ is C₁₋₆ alkyl.

In some embodiments, R⁴ is —C₁ alkylene-(C₆ arylene)-N(H)C(O)R⁵⁸ and R⁵⁸is selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, 5- to10-membered heteroaryl, and 5- to 10-membered heterocycloalkyl. In someembodiments, R⁴ is —C₁ alkylene-(C₆ arylene)-N(H)C(O)R⁵⁸ and R⁵⁸ isselected from the group consisting of C₆₋₁₀ aryl and 5- to 10-memberedheterocycloalkyl. In some embodiments, R⁴ is —C₁ alkylene-(C₆arylene)-N(H)C(O)R⁵⁸ and R⁵⁸ is selected from the group consisting of C₆aryl, 5- to 6-membered heteroaryl, and 5- to 6-memberedheterocycloalkyl. In some embodiments, R⁴ is —C₁ alkylene-(C₆arylene)-N(H)C(O)R⁵⁸ and R⁵⁸ is pyrrolidinyl. In other embodiments, R⁴is —C₁ alkylene-(C₆ arylene)-N(H)C(O)R⁵⁸ and R⁵⁸ is phenyl.

In some embodiments, R⁴ is

wherein R¹⁰³ is selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀aryl, 5- to 10-membered heteroaryl, and 5- to 10-memberedheterocycloalkyl, wherein the C₁₋₆ alkyl is optionally substituted withone or more substituents each independently selected from the groupconsisting of halogen, hydroxy, —NO₂, and C₁₋₆ alkoxy, and wherein theC₆₋₁₀ aryl, 5- to 10-membered heteroaryl, and 5- to 10-memberedheterocycloalkyl are optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen, hydroxy, —NO₂, and C₁₋₆ alkoxy, and wherein n⁵ is 0, 1, 2, 3,or 4.

In some embodiments, R⁴ is

wherein X¹ is CH, CR¹⁰⁴, or N, X² is CH, CR¹⁰⁵, or N, X³ is CH, CR¹⁰⁶,or N, X⁴ is CH, CR¹⁰⁷, or N, and X⁵ is CH, CR¹⁰⁸, or N, and each ofR¹⁰⁴, R¹⁰⁵, R¹⁰⁶, R¹⁰⁷, and R¹⁰⁸ is independently selected from thegroup consisting of halogen, hydroxy, —NO₂, and C₁₋₆alkoxy.

In some embodiments, R⁴ is

wherein R¹⁰⁹ is selected from the group consisting of H, halogen,hydroxy, —NO₂, and C₁₋₆alkoxy. In other embodiments, R¹⁰⁹ is H.

In some embodiments, R⁴ is —(C₆₋₁₀ arylene)-N(R⁶²)C(O)NR⁶⁰R⁶¹ or —C₁₋₆alkylene-(C₆₋₁₀ arylene)-N(R⁶²)C(O)NR⁶⁰R⁶¹, wherein each of R⁶⁰ and R⁶¹is independently selected from the group consisting of H, C₁₋₆ alkyl,C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the C₁₋₆ alkyl isoptionally substituted with one or more substituents, and wherein theC₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally substitutedwith one or more substituents, and wherein R⁶² is H or C₁₋₆alkyl.

In some embodiments, R⁴ is —(C₆₋₁₀ arylene)-N(R⁶²)C(O)NR⁶⁰R⁶¹ or —C₁₋₆alkylene-(C₆₋₁₀ arylene)-N(R⁶²)C(O)NR⁶⁰R⁶¹, wherein R⁶⁰ is selected fromthe group consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl, and R⁶¹ is selected from the group consisting of C₁₋₆ alkyl,C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the C₁₋₆alkyl ofR⁶⁰ or R⁶¹ is optionally substituted with one or more substituents, andwherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl of R⁶⁰ or R⁶¹are optionally substituted with one or more substituents, and whereinR⁶² is H or C₁₋₆alkyl.

In some embodiments, R⁴ is —(C₆₋₁₀ arylene)-N(R⁶²)C(O)NR⁶⁰R⁶¹ or —C₁₋₆alkylene-(C₆₋₁₀ arylene)-N(R⁶²)C(O)NR⁶⁰R⁶¹, wherein each of R⁶⁰ and R⁶¹is independently selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀aryl, and 5- to 10-membered heteroaryl, wherein the C₁₋₆alkyl isoptionally substituted with one or more substituents, and wherein theC₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally substitutedwith one or more substituents, and wherein R⁶² is H or C₁₋₆alkyl.

In some embodiments, R⁴ is —(C₆₋₁₀ arylene)-N(R⁶²)C(O)NR⁶⁰R⁶¹ or —C₁₋₆alkylene-(C₆₋₁₀ arylene)-N(R⁶²)C(O)NR⁶⁰R⁶¹, wherein each of R⁶⁰ and R⁶¹is independently selected from the group consisting of H, C₁₋₆alkyl,C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the C₁₋₆alkyl isoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, —OH, —NO₂, C₁₋₆alkoxy,C₁₋₆ haloalkoxy, —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)₂, —C₁₋₆ alkyl,haloC₁₋₆ alkyl, aminoC₁₋₆ alkyl, C₆₋₁₀ aryl, 5- to 10-memberedheteroaryl, 5- to 10-membered heterocycloalkyl, C₅₋₁₀ cycloalkyl, azido,—CN, —COR²⁰⁰ wherein R²⁰⁰ is C₁₋₆ alkyl or C₆₋₁₀ aryl, —CO₂R²⁰¹ whereinR²⁰¹ is H or C₁₋₆ alkyl, —CONR²⁰²R²⁰³ wherein R²⁰² and R²⁰³ is H or C₁₋₆alkyl, —NR²⁰⁴COR²⁰⁵ wherein R²⁰⁴ is H or C₁₋₆ alkyl and R²⁰⁵ is C₁₋₆alkyl, —SO₂NR²⁰⁶R²⁰⁷ wherein R²⁰⁶ and R²⁰⁷ is H or C₁₋₆ alkyl, and—NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸ is H or C₁₋₆ alkyl and R²⁰⁹ is C₁₋₆ alkyl,and wherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl areoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, —OH, —NO₂, C₁₋₆ alkoxy,C₁₋₆ haloalkoxy, —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)₂, —C₁₋₆ alkyl,haloC₁₋₆ alkyl, aminoC₁₋₆ alkyl, C₆₋₁₀ aryl, 5- to 10-memberedheteroaryl, 5- to 10-membered heterocycloalkyl, C₅₋₁₀ cycloalkyl, azido,—CN, —COR²⁰⁰ wherein R²⁰⁰ is C₁₋₆ alkyl or C₆₋₁₀ aryl, —CO₂R²⁰¹ whereinR²⁰¹ is H or C₁₋₆ alkyl, —CONR²⁰²R²⁰³ wherein R²⁰² and R²⁰³ is H or C₁₋₆alkyl, —NR²⁰⁴COR²⁰⁵ wherein R²⁰⁴ is H or C₁₋₆ alkyl and R²⁰⁵ is C₁₋₆alkyl, —SO₂NR²⁰⁶R²⁰⁷ wherein R²⁰⁶ and R²⁰⁷ is H or C₁₋₆ alkyl, and—NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸ is H or C₁₋₆ alkyl and R²⁰⁹ is C₁₋₆ alkyl,and wherein R⁶² is H or C₁₋₆alkyl.

In some embodiments, R⁴ is —(C₆₋₁₀ arylene)-N(R⁶²)C(O)NR⁶⁰R⁶¹ or —C₁₋₆alkylene-(C₆₋₁₀ arylene)-N(R⁶²)C(O)NR⁶⁰R⁶¹, wherein R⁶⁰ is selected fromthe group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl, and R⁶¹ is selected from the group consisting of C₁₋₆ alkyl,C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the C₁₋₆alkyl ofR⁶⁰ or R⁶¹ is optionally substituted with one or more substituents eachindependently selected from the group consisting of halogen, —OH, —NO₂,C₁₋₆alkoxy, C₁₋₆ haloalkoxy, —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)₂,—C₁₋₆ alkyl, haloC₁₋₆ alkyl, aminoC₁₋₆ alkyl, C₆₋₁₀ aryl, 5- to10-membered heteroaryl, 5- to 10-membered heterocycloalkyl, C₅₋₁₀cycloalkyl, azido, —CN, —COR²⁰⁰ wherein R²⁰⁰ is C₁₋₆ alkyl or C₆₋₁₀aryl, —CO₂R²⁰¹ wherein R²⁰¹ is H or C₁₋₆ alkyl, —CONR²⁰²R²⁰³ whereinR²⁰² and R²⁰³ is H or C₁₋₆ alkyl, —NR²⁰⁴COR²⁰⁵ wherein R²⁰⁴ is H or C₁₋₆alkyl and R²⁰⁵ is C₁₋₆ alkyl, —SO₂NR²⁰⁶R²⁰⁷ wherein R²⁰⁶ and R²⁰⁷ is Hor C₁₋₆ alkyl, and —NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸ is H or C₁₋₆ alkyl andR²⁰⁹ is C₁₋₆ alkyl, and wherein the C₆₋₁₀ aryl and 5- to 10-memberedheteroaryl of R⁶⁰ or R⁶¹ are optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen, —OH, —NO₂, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, —NH₂, —NH(C₁₋₆ alkyl),—N(C₁₋₆ alkyl)₂, —C₁₋₆ alkyl, haloC₁₋₆ alkyl, aminoC₁₋₆ alkyl, C₆₋₁₀aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocycloalkyl,C₅₋₁₀ cycloalkyl, azido, —CN, —COR²⁰⁰ wherein R²⁰⁰ is C₁₋₆ alkyl orC₆₋₁₀ aryl, —CO₂R²⁰¹ wherein R²⁰¹ is H or C₁₋₆ alkyl, —CONR²⁰²R²⁰³wherein R²⁰² and R²⁰³ is H or C₁₋₆ alkyl, —NR²⁰⁴COR²⁰⁵ wherein R²⁰⁴ is Hor C₁₋₆ alkyl and R²⁰⁵ is C₁₋₆ alkyl, —SO₂NR²⁰⁶R²⁰⁷ wherein R²⁰⁶ andR²⁰⁷ is H or C₁₋₆ alkyl, and —NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸ is H or C₁₋₆alkyl and R²⁰⁹ is C₁₋₆ alkyl, and wherein R⁶² is H or C₁₋₆alkyl.

In some embodiments, R⁴ is —(C₆₋₁₀ arylene)-N(R⁶²)C(O)NR⁶⁰R⁶¹ or —C₁₋₆alkylene-(C₆₋₁₀ arylene)-N(R⁶²)C(O)NR⁶⁰R⁶¹, wherein each of R⁶⁰ and R⁶¹is independently selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀aryl, and 5- to 10-membered heteroaryl, wherein the C₁₋₆alkyl isoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, —OH, —NO₂, C₁₋₆alkoxy,C₁₋₆ haloalkoxy, —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)₂, —C₁₋₆ alkyl,haloC₁₋₆ alkyl, aminoC₁₋₆ alkyl, C₆₋₁₀ aryl, 5- to 10-memberedheteroaryl, 5- to 10-membered heterocycloalkyl, C₅₋₁₀ cycloalkyl, azido,—CN, —COR²⁰⁰ wherein R²⁰⁰ is C₁₋₆ alkyl or C₆₋₁₀ aryl, —CO₂R²⁰¹ whereinR²⁰¹ is H or C₁₋₆ alkyl, —CONR²⁰²R²⁰³ wherein R²⁰² and R²⁰³ is H or C₁₋₆alkyl, —NR²⁰⁴COR²⁰⁵ wherein R²⁰⁴ is H or C₁₋₆ alkyl and R²⁰⁵ is C₁₋₆alkyl, —SO₂NR²⁰⁶R²⁰⁷ wherein R²⁰⁶ and R²⁰⁷ is H or C₁₋₆ alkyl, and—NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸ is H or C₁₋₆ alkyl and R²⁰⁹ is C₁₋₆ alkyl,and wherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl areoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, —OH, —NO₂, C₁₋₆ alkoxy,C₁₋₆ haloalkoxy, —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)₂, —C₁₋₆ alkyl,haloC₁₋₆ alkyl, aminoC₁₋₆ alkyl, C₆₋₁₀ aryl, 5- to 10-memberedheteroaryl, 5- to 10-membered heterocycloalkyl, C₅₋₁₀ cycloalkyl, azido,—CN, —COR²⁰⁰ wherein R²⁰⁰ is C₁₋₆ alkyl or C₆₋₁₀ aryl, —CO₂R²⁰¹ whereinR²⁰¹ is H or C₁₋₆ alkyl, —CONR²⁰²R²⁰³ wherein R²⁰² and R²⁰³ is H or C₁₋₆alkyl, —NR²⁰⁴COR²⁰⁵ wherein R²⁰⁴ is H or C₁₋₆ alkyl and R²⁰⁵ is C₁₋₆alkyl, —SO₂NR²⁰⁶R²⁰⁷ wherein R²⁰⁶ and R²⁰⁷ is H or C₁₋₆ alkyl, and—NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸ is H or C₁₋₆ alkyl and R²⁰⁹ is C₁₋₆ alkyl,and wherein R⁶² is H or C₁₋₆alkyl.

In some embodiments, R⁴ is —(C₆₋₁₀ arylene)-N(H)C(O)NR⁶⁰R⁶¹ or —C₁₋₆alkylene-(C₆₋₁₀ arylene)-N(H)C(O)NR⁶⁰R⁶¹, wherein each of R⁶⁰ and R⁶¹ isindependently selected from the group consisting of H, C₁₋₆ alkyl, C₆₋₁₀aryl, and 5- to 10-membered heteroaryl, wherein the C₁₋₆alkyl isoptionally substituted with one or more substituents, and wherein theC₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally substitutedwith one or more substituents.

In some embodiments, R⁴ is —(C₆₋₁₀ arylene)-N(H)C(O)NR⁶⁰R⁶¹ or —C₁₋₆alkylene-(C₆₋₁₀ arylene)-N(H)C(O)NR⁶⁰R⁶¹, wherein R⁶⁰ is selected fromthe group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl, and R⁶¹ is selected from the group consisting of C₁₋₆alkyl,C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the C₁₋₆alkyl ofR⁶⁰ or R⁶¹ is optionally substituted with one or more substituents, andwherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl of R⁶⁰ or R⁶¹are optionally substituted with one or more substituents.

In some embodiments, R⁴ is —(C₆₋₁₀ arylene)-N(H)C(O)NR⁶⁰R⁶¹ or —C₁₋₆alkylene-(C₆₋₁₀ arylene)-N(H)C(O)NR⁶⁰R⁶¹, wherein each of R⁶⁰ and R⁶¹ isindependently selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀aryl, and 5- to 10-membered heteroaryl, wherein the C₁₋₆alkyl isoptionally substituted with one or more substituents, and wherein theC₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally substitutedwith one or more substituents.

In some embodiments, R⁴ is —(C₆₋₁₀ arylene)-N(H)C(O)NR⁶⁰R⁶¹ or —C₁₋₆alkylene-(C₆₋₁₀ arylene)-N(H)C(O)NR⁶⁰R⁶¹, wherein each of R⁶⁰ and R⁶¹ isindependently selected from the group consisting of H, C₁₋₆alkyl, C₆₋₁₀aryl, and 5- to 10-membered heteroaryl, wherein the C₁₋₆alkyl isoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, —OH, —NO₂, C₁₋₆alkoxy,C₁₋₆ haloalkoxy, —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)₂, —C₁₋₆ alkyl,haloC₁₋₆ alkyl, aminoC₁₋₆ alkyl, C₆₋₁₀ aryl, 5- to 10-memberedheteroaryl, 5- to 10-membered heterocycloalkyl, C₅₋₁₀ cycloalkyl, azido,—CN, —COR²⁰⁰ wherein R²⁰⁰ is C₁₋₆ alkyl or C₆₋₁₀ aryl, —CO₂R²⁰¹ whereinR²⁰¹ is H or C₁₋₆ alkyl, —CONR²⁰²R²⁰³ wherein R²⁰² and R²⁰³ is H or C₁₋₆alkyl, —NR²⁰⁴COR²⁰⁵ wherein R²⁰⁴ is H or C₁₋₆ alkyl and R²⁰⁵ is C₁₋₆alkyl, —SO₂NR²⁰⁶R²⁰⁷ wherein R²⁰⁶ and R²⁰⁷ is H or C₁₋₆ alkyl, and—NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸ is H or C₁₋₆ alkyl and R²⁰⁹ is C₁₋₆ alkyl,and wherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl areoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, —OH, —NO₂, C₁₋₆ alkoxy,C₁₋₆ haloalkoxy, —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)₂, —C₁₋₆ alkyl,haloC₁₋₆ alkyl, aminoC₁₋₆ alkyl, C₆₋₁₀ aryl, 5- to 10-memberedheteroaryl, 5- to 10-membered heterocycloalkyl, C₅₋₁₀ cycloalkyl, azido,—CN, —COR²⁰⁰ wherein R²⁰⁰ is C₁₋₆ alkyl or C₆₋₁₀ aryl, —CO₂R²⁰¹ whereinR²⁰¹ is H or C₁₋₆ alkyl, —CONR²⁰²R²⁰³ wherein R²⁰² and R²⁰³ is H or C₁₋₆alkyl, —NR²⁰⁴COR²⁰⁵ wherein R²⁰⁴ is H or C₁₋₆ alkyl and R²⁰⁵ is C₁₋₆alkyl, —SO₂NR²⁰⁶R²⁰⁷ wherein R²⁰⁶ and R²⁰⁷ is H or C₁₋₆ alkyl, and—NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸ is H or C₁₋₆ alkyl and R²⁰⁹ is C₁₋₆ alkyl.

In some embodiments, R⁴ is —(C₆₋₁₀ arylene)-N(H)C(O)NR⁶⁰R⁶¹ or —C₁₋₆alkylene-(C₆₋₁₀ arylene)-N(H)C(O)NR⁶⁰R⁶¹, wherein R⁶⁰ is selected fromthe group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl, and R⁶¹ is selected from the group consisting of C₁₋₆alkyl,C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the C₁₋₆alkyl ofR⁶⁰ or R⁶¹ is optionally substituted with one or more substituents eachindependently selected from the group consisting of halogen, —OH, —NO₂,C₁₋₆alkoxy, C₁₋₆ haloalkoxy, —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)₂,—C₁₋₆ alkyl, haloC₁₋₆ alkyl, aminoC₁₋₆ alkyl, C₆₋₁₀ aryl, 5- to10-membered heteroaryl, 5- to 10-membered heterocycloalkyl, C₅₋₁₀cycloalkyl, azido, —CN, —COR²⁰⁰ wherein R²⁰⁰ is C₁₋₆ alkyl or C₆₋₁₀aryl, —CO₂R²⁰¹ wherein R²⁰¹ is H or C₁₋₆ alkyl, —CONR²⁰²R²⁰³ whereinR²⁰² and R²⁰³ is H or C₁₋₆ alkyl, —NR²⁰⁴COR²⁰⁵ wherein R²⁰⁴ is H or C₁₋₆alkyl and R²⁰⁵ is C₁₋₆ alkyl, —SO₂NR²⁰⁶R²⁰⁷ wherein R²⁰⁶ and R²⁰⁷ is Hor C₁₋₆ alkyl, and —NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸ is H or C₁₋₆ alkyl andR²⁰⁹ is C₁₋₆ alkyl, and wherein the C₆₋₁₀ aryl and 5- to 10-memberedheteroaryl of R⁶⁰ or R⁶¹ are optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen, —OH, —NO₂, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, —NH₂, —NH(C₁₋₆ alkyl),—N(C₁₋₆ alkyl)₂, —C₁₋₆ alkyl, haloC₁₋₆ alkyl, aminoC₁₋₆ alkyl, C₆₋₁₀aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocycloalkyl,C₅₋₁₀ cycloalkyl, azido, —CN, —COR²⁰⁰ wherein R²⁰⁰ is C₁₋₆ alkyl orC₆₋₁₀ aryl, —CO₂R²⁰¹ wherein R²⁰¹ is H or C₁₋₆ alkyl, —CONR²⁰²R²⁰³wherein R²² and R²⁰³ is H or C₁₋₆ alkyl, —NR²⁰⁴COR²⁰⁵ wherein R²⁰⁴ is Hor C₁₋₆ alkyl and R²⁰⁵ is C₁₋₆ alkyl, —SO₂NR²⁰⁶R²⁰⁷ wherein R²⁰⁶ andR²⁰⁷ is H or C₁₋₆ alkyl, and —NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸ is H or C₁₋₆alkyl and R²⁰⁹ is C₁₋₆ alkyl.

In some embodiments, R⁴ is —(C₆₋₁₀ arylene)-N(H)C(O)NR⁶⁰R⁶¹ or —C₁₋₆alkylene-(C₆₋₁₀ arylene)-N(H)C(O)NR⁶⁰R⁶¹, wherein each of R⁶⁰ and R⁶¹ isindependently selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀aryl, and 5- to 10-membered heteroaryl, wherein the C₁₋₆ alkyl isoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, —OH, —NO₂, C₁₋₆alkoxy,C₁₋₆ haloalkoxy, —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)₂, —C₁₋₆ alkyl,haloC₁₋₆ alkyl, aminoC₁₋₆ alkyl, C₆₋₁₀ aryl, 5- to 10-memberedheteroaryl, 5- to 10-membered heterocycloalkyl, C₅₋₁₀ cycloalkyl, azido,—CN, —COR²⁰⁰ wherein R²⁰⁰ is C₁₋₆ alkyl or C₆₋₁₀ aryl, —CO₂R²⁰¹ whereinR²⁰¹ is H or C₁₋₆ alkyl, —CONR²⁰²R²⁰³ wherein R²⁰² and R²⁰³ is H or C₁₋₆alkyl, —NR²⁰⁴COR²⁰⁵ wherein R²⁰⁴ is H or C₁₋₆ alkyl and R²⁰⁵ is C₁₋₆alkyl, —SO₂NR²⁰⁶R²⁰⁷ wherein R²⁰⁶ and R²⁰⁷ is H or C₁₋₆ alkyl, and—NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸ is H or C₁₋₆ alkyl and R²⁰⁹ is C₁₋₆ alkyl,and wherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl areoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, —OH, —NO₂, C₁₋₆ alkoxy,C₁₋₆ haloalkoxy, —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)₂, —C₁₋₆ alkyl,haloC₁₋₆ alkyl, aminoC₁₋₆ alkyl, C₆₋₁₀ aryl, 5- to 10-memberedheteroaryl, 5- to 10-membered heterocycloalkyl, C₅₋₁₀ cycloalkyl, azido,—CN, —COR²⁰⁰ wherein R²⁰⁰ is C₁₋₆ alkyl or C₆₋₁₀ aryl, —CO₂R²⁰¹ whereinR²⁰¹ is H or C₁₋₆ alkyl, —CONR²⁰²R²⁰³ wherein R²⁰² and R²⁰³ is H or C₁₋₆alkyl, —NR²⁰⁴COR²⁰⁵ wherein R²⁰⁴ is H or C₁₋₆ alkyl and R²⁰⁵ is C₁₋₆alkyl, —SO₂NR²⁰⁶R²⁰⁷ wherein R²⁰⁶ and R²⁰⁷ is H or C₁₋₆ alkyl, and—NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸ is H or C₁₋₆ alkyl and R²⁰⁹ is C₁₋₆ alkyl.

In some embodiments, R⁴ is —C₁₋₂ alkylene-(C₆ arylene)-N(H)C(O)NR⁶⁰R⁶¹,wherein R⁶⁰ is selected from the group consisting of H, C₁₋₆alkyl, C₆₋₁₀aryl, and 5- to 10-membered heteroaryl, and R⁶¹ is selected from thegroup consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl. In some embodiments, R⁴ is —C₁₋₂ alkylene-(C₆arylene)-N(H)C(O)NR⁶⁰R⁶¹ and R⁶⁰ is H and R⁶¹ is phenyl.

In some embodiments, R⁴ is

wherein each of R¹¹⁰ and R¹¹¹ is independently selected from the groupconsisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl, wherein the C₁₋₆alkyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl and 5-to 10-membered heteroaryl are optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein n⁶ is 0, 1, 2, 3, or 4.

In some embodiments, R⁴ is

wherein R¹¹⁰ is selected from the group consisting of H, C₁₋₆alkyl,C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, and R¹¹¹ is selected fromthe group consisting of C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl, wherein the C₁₋₆ alkyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen, —OH, —NO₂, and C₁₋₆ alkoxy, and wherein the C₆₋₁₀ aryl and5- to 10-membered heteroaryl are optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein n⁶ is 0, 1, 2, 3, or 4.In some embodiments, R¹¹⁰ is selected from the group consisting of H,C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, and R¹¹¹ isselected from the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to10-membered heteroaryl.

In some embodiments, R⁴ is

wherein each of R¹⁰ and R¹¹ is independently selected from the groupconsisting of C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl,wherein the C₁₋₆alkyl is optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl and 5- to10-membered heteroaryl are optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein n⁶ is 0, 1, 2, 3, or 4.

In some embodiments, R⁴ is

wherein R¹¹² is selected from the group consisting of H, C₁₋₆ alkyl,C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the C₁₋₆ alkyl isoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, —OH, —NO₂, andC₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl and 5- to 10-membered heteroarylare optionally substituted with one or more substituents eachindependently selected from the group consisting of halogen, —OH, —NO₂,and C₁₋₆alkoxy, and wherein n⁷ is 0, 1, 2, 3, or 4.

In some embodiments, R⁴ is

wherein R¹¹² is selected from the group consisting of C₁₋₆ alkyl, C₆₋₁₀aryl, and 5- to 10-membered heteroaryl, wherein the C₁₋₆ alkyl isoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, —OH, —NO₂, andC₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl and 5- to 10-membered heteroarylare optionally substituted with one or more substituents eachindependently selected from the group consisting of halogen, —OH, —NO₂,and C₁₋₆alkoxy, and wherein n⁷ is 0, 1, 2, 3, or 4. In some embodiments,R¹¹² is selected from the group consisting of C₁₋₆ alkyl, C₆₋₁₀ aryl,and 5- to 10-membered heteroaryl.

In some embodiments, R⁴ is

wherein X⁶ is CH, CR¹¹³ or N, X⁷ is CH, CR¹¹⁴ or N, X⁸ is CH, CR¹¹⁵ orN, X⁹ is CH, CR¹¹⁶ or N, and X¹⁰ is CH, CR¹¹⁷ or N, and each R¹¹³, R¹¹⁴,R¹¹⁵, R¹¹⁶, and R¹¹⁷ is independently selected from the group consistingof halogen, hydroxy, —NO₂, and C₁₋₆ alkoxy.

In some embodiments, R⁴ is

wherein R¹¹⁸ is selected from the group consisting of H, halogen,hydroxy, —NO₂, and C₁₋₆alkoxy. In other embodiments, R¹¹⁸ is H.

In some embodiments, R⁴ is —(C₆₋₁₀ arylene)-N(R⁶⁴)SO₂R⁶³ or —C₁₋₆alkylene-(C₆₋₁₀ arylene)-N(R⁶⁴)SO₂R⁶³, wherein R⁶³ is selected from thegroup consisting of C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl, wherein the C₁₋₆alkyl is optionally substituted with one ormore substituents, and wherein the C₆₋₁₀ aryl and 5- to 10-memberedheteroaryl are optionally substituted with one or more substituents, andwherein R⁶⁴ is H or C₁₋₆alkyl.

In some embodiments, R⁴ is —(C₆₋₁₀ arylene)-N(R⁶⁴)SO₂R⁶³ or —C₁₋₆alkylene-(C₆₋₁₀ arylene)-N(R⁶⁴)SO₂R⁶³, wherein R⁶³ is selected from thegroup consisting of C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl, wherein the C₁₋₆alkyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen, —OH, —NO₂, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, —NH₂, —NH(C₁₋₆alkyl), —N(C₁₋₆ alkyl)₂, —C₁₋₆ alkyl, haloC₁₋₆ alkyl, aminoC₁₋₆ alkyl,C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, 5- to 10-memberedheterocycloalkyl, C₅₋₁₀ cycloalkyl, azido, —CN, —COR²⁰⁰ wherein R²⁰⁰ isC₁₋₆ alkyl or C₆₋₁₀ aryl, —CO₂R²⁰¹ wherein R²⁰¹ is H or C₁₋₆ alkyl,—CONR²⁰²R²⁰³ wherein R²⁰² and R²⁰³ is H or C₁₋₆ alkyl, —NR²⁰⁴COR²⁰⁵wherein R²⁰⁴ is H or C₁₋₆ alkyl and R²⁰⁵ is C₁₋₆ alkyl, —SO₂NR²⁰⁶R²⁰⁷wherein R²⁰⁶ and R²⁰⁷ is H or C₁₋₆ alkyl, and —NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸is H or C₁₋₆ alkyl and R²⁰⁹ is C₁₋₆ alkyl, and wherein the C₆₋₁₀ aryland 5- to 10-membered heteroaryl are optionally substituted with one ormore substituents each independently selected from the group consistingof halogen, —OH, —NO₂, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, —NH₂, —NH(C₁₋₆alkyl), —N(C₁₋₆ alkyl)₂, —C₁₋₆ alkyl, haloC₁₋₆ alkyl, aminoC₁₋₆ alkyl,C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, 5- to 10-memberedheterocycloalkyl, C₅₋₁₀ cycloalkyl, azido, —CN, —COR²⁰⁰ wherein R²⁰⁰ isC₁₋₆ alkyl or C₆₋₁₀ aryl, —CO₂R²⁰¹ wherein R²⁰¹ is H or C₁₋₆ alkyl,—CONR²⁰²R²⁰³ wherein R²⁰² and R²⁰³ is H or C₁₋₆ alkyl, —NR²⁰⁴COR²⁰⁵wherein R²⁰⁴ is H or C₁₋₆ alkyl and R²⁰⁵ is C₁₋₆ alkyl, —SO₂NR²⁰⁶R²⁰⁷wherein R²⁰⁶ and R²⁰⁷ is H or C₁₋₆ alkyl, and —NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸is H or C₁₋₆ alkyl and R²⁰⁹ is C₁₋₆ alkyl, and wherein R⁶⁴ is H or C₁₋₆alkyl.

In some embodiments, R⁴ is —(C₆₋₁₀ arylene)-N(H)SO₂R⁶³ or —C₁₋₆alkylene-(C₆₋₁₀ arylene)-N(H)SO₂R⁶³, wherein R⁶³ is selected from thegroup consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl, wherein the C₁₋₆alkyl is optionally substituted with one ormore substituents, and wherein the C₆₋₁₀ aryl and 5- to 10-memberedheteroaryl are optionally substituted with one or more substituents.

In some embodiments, R⁴ is —(C₆₋₁₀ arylene)-N(H)SO₂R⁶³ or —C₁₋₆alkylene-(C₆₋₁₀ arylene)-N(H)SO₂R⁶³, wherein R⁶³ is selected from thegroup consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl, wherein the C₁₋₆alkyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen, —OH, —NO₂, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, —NH₂, —NH(C₁₋₆alkyl), —N(C₁₋₆ alkyl)₂, —C₁₋₆ alkyl, haloC₁₋₆ alkyl, aminoC₁₋₆ alkyl,C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, 5- to 10-memberedheterocycloalkyl, C₅₋₁₀ cycloalkyl, azido, —CN, —COR²⁰⁰ wherein R²⁰⁰ isC₁₋₆ alkyl or C₆₋₁₀ aryl, —CO₂R²⁰¹ wherein R²⁰¹ is H or C₁₋₆ alkyl,—CONR²⁰²R²⁰³ wherein R²⁰² and R²⁰³ is H or C₁₋₆ alkyl, —NR²⁰⁴COR²⁰⁵wherein R²⁰⁴ is H or C₁₋₆ alkyl and R²⁰⁵ is C₁₋₆ alkyl, —SO₂NR²⁰⁶R²⁰⁷wherein R²⁰⁶ and R²⁰⁷ is H or C₁₋₆ alkyl, and —NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸is H or C₁₋₆ alkyl and R²⁰⁹ is C₁₋₆ alkyl, and wherein the C₆₋₁₀ aryland 5- to 10-membered heteroaryl are optionally substituted with one ormore substituents each independently selected from the group consistingof halogen, —OH, —NO₂, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, —NH₂, —NH(C₁₋₆alkyl), —N(C₁₋₆ alkyl)₂, —C₁₋₆ alkyl, haloC₁₋₆ alkyl, aminoC₁₋₆ alkyl,C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, 5- to 10-memberedheterocycloalkyl, C₅₋₁₀ cycloalkyl, azido, —CN, —COR²⁰⁰ wherein R²⁰⁰ isC₁₋₆ alkyl or C₆₋₁₀ aryl, —CO₂R²⁰¹ wherein R²⁰¹ is H or C₁₋₆ alkyl,—CONR²⁰²R²⁰³ wherein R²⁰² and R²⁰³ is H or C₁₋₆ alkyl, —NR²⁰⁴COR²⁰⁵wherein R²⁰⁴ is H or C₁₋₆ alkyl and R²⁰⁵ is C₁₋₆ alkyl, —SO₂NR²⁰⁶R²⁰⁷wherein R²⁰⁶ and R²⁰⁷ is H or C₁₋₆ alkyl, and —NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸is H or C₁₋₆ alkyl and R²⁰⁹ is C₁₋₆ alkyl.

In some embodiments, R⁴ is —C₁₋₂ alkylene-(C₆ arylene)-N(H)SO₂R⁶³ andR⁶³ is C₆ aryl optionally substituted with one or more substituents eachindependently selected from the group consisting of halogen, hydroxy,—NO₂, and C₁₋₆ alkoxy. In other embodiments, R⁴ is —C₁₋₂ alkylene-(C₆arylene)-N(H)SO₂R⁶³ and R⁶³ is phenyl. In some embodiments, R⁴ is —C₁alkylene-(C₆ arylene)-N(H)SO₂R⁶³ and R⁶³ is phenyl.

In some embodiments, R⁴ is:

wherein R¹¹⁹ is selected from the group consisting of C₁₋₆ alkyl, C₆₋₁₀aryl, and 5- to 10-membered heteroaryl, wherein the C₁₋₆ alkyl isoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, hydroxy, —NO₂, and C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl areoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, hydroxy, —NO₂, andC₁₋₆alkoxy, and wherein n⁸ is 0, 1, 2, 3, or 4. In other embodiments,R¹¹⁹ is selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and5- to 10-membered heteroaryl.

In some embodiments, R⁴ is:

wherein X₁₁ is CH, CR¹²⁰ or N, X¹² is CH, CR¹²¹ or N, X¹³ is CH, CR¹²²or N, X¹⁴ is CH, CR¹²³ or N, and X¹⁵ is CH, CR¹²⁴ or N, and each ofR¹²⁰, R¹²¹, R¹²², R¹²³ and R¹²⁴ is independently selected from the groupconsisting of halogen, hydroxy, —NO₂, and C₁₋₆ alkoxy.

In some embodiments, R⁴ is:

wherein R¹²⁵ is selected from the group consisting of H, halogen,hydroxy, —NO₂, and C₁₋₆alkoxy. In some embodiments, R¹²⁵ is H.

In some embodiments, R⁴ is —(C₆₋₁₀ arylene)-SO₂NR⁶⁵R⁶⁶ or —C₁₋₆alkylene-(C₆₋₁₀ arylene)-SO₂NR⁶⁵R⁶⁶, wherein each of R⁶⁵ and R⁶⁶ isindependently selected from the group consisting of H, C₁₋₆alkyl, C₆₋₁₀aryl, and 5- to 10-membered heteroaryl, wherein the C₁₋₆alkyl isoptionally substituted with one or more substituents, and wherein theC₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally substitutedwith one or more substituents.

In some embodiments, R⁴ is —(C₆₋₁₀ arylene)-SO₂NR⁶⁵R⁶⁶ or —C₁₋₆alkylene-(C₆₋₁₀ arylene)-SO₂NR⁶⁵R⁶⁶, wherein each of R⁶⁵ and R⁶⁶ isindependently selected from the group consisting of H, C₁₋₆alkyl, C₆₋₁₀aryl, and 5- to 10-membered heteroaryl, wherein the C₁₋₆ alkyl isoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, —OH, —NO₂, C₁₋₆alkoxy,C₁₋₆ haloalkoxy, —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)₂, —C₁₋₆ alkyl,haloC₁₋₆ alkyl, aminoC₁₋₆ alkyl, C₆₋₁₀ aryl, 5- to 10-memberedheteroaryl, 5- to 10-membered heterocycloalkyl, C₅₋₁₀ cycloalkyl, azido,—CN, —COR²⁰⁰ wherein R²⁰⁰ is C₁₋₆ alkyl or C₆₋₁₀ aryl, —CO₂R²⁰¹ whereinR²⁰¹ is H or C₁₋₆ alkyl, —CONR²⁰²R²⁰³ wherein R²⁰² and R²⁰³ is H or C₁₋₆alkyl, —NR²⁰⁴COR²⁰⁵ wherein R²⁰⁴ is H or C₁₋₆ alkyl and R²⁰⁵ is C₁₋₆alkyl, —SO₂NR²⁰⁶R²⁰⁷ wherein R²⁰⁶ and R²⁰⁷ is H or C₁₋₆ alkyl, and—NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸ is H or C₁₋₆ alkyl and R²⁰⁹ is C₁₋₆ alkyl,and wherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl areoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, —OH, —NO₂, C₁₋₆alkoxy,C₁₋₆ haloalkoxy, —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)₂, —C₁₋₆ alkyl,haloC₁₋₆ alkyl, aminoC₁₋₆ alkyl, C₆₋₁₀ aryl, 5- to 10-memberedheteroaryl, 5- to 10-membered heterocycloalkyl, C₅₋₁₀ cycloalkyl, azido,—CN, —COR²⁰⁰ wherein R²⁰⁰ is C₁₋₆ alkyl or C₆₋₁₀ aryl, —CO₂R²⁰¹ whereinR²⁰¹ is H or C₁₋₆ alkyl, —CONR²⁰²R²⁰³ wherein R²⁰² and R²⁰³ is H or C₁₋₆alkyl, —NR²⁰⁴COR²⁰⁵ wherein R²⁰⁴ is H or C₁₋₆ alkyl and R²⁰⁵ is C₁₋₆alkyl, —SO₂NR²⁰⁶R²⁰⁷ wherein R²⁰⁶ and R²⁰⁷ is H or C₁₋₆ alkyl, and—NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸ is H or C₁₋₆ alkyl and R²⁰⁹ is C₁₋₆ alkyl.

In some embodiments, R⁴ is

wherein each of R¹²⁶ and R¹²⁷ is independently selected from the groupconsisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl, wherein the C₁₋₆alkyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl and 5-to 10-membered heteroaryl are optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein n⁹ is 0, 1, 2, 3, or 4.In some embodiments, each of R¹²⁶ and R¹²⁷ is independently selectedfrom the group consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to10-membered heteroaryl.

In some embodiments, R⁴ is

wherein X¹⁶ is CH, CR¹²⁸ or N, X¹⁷ is CH, CR¹²⁹ or N, X¹⁸ is CH, CR¹³⁰or N, X¹⁹ is CH, CR¹³¹ or N, and X²⁰ is CH, CR¹³² or N, and each ofR¹²⁸, R¹²⁹, R¹³⁰, R¹³¹ and R¹³² is independently selected from the groupconsisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy.

In some embodiments, R⁴ is

wherein R¹³³ is selected from the group consisting of H, halogen, —OH,—NO₂, and C₁₋₆alkoxy. In other embodiments, R¹³³ is H.

In some embodiments, R⁴ is —(C₆₋₁₀ arylene)-(C₁₋₆ alkylene)-NR⁶⁷R⁶⁸ or—C₁₋₆ alkylene-(C₆₋₁₀ arylene)-(C₁₋₆ alkylene)-NR⁶⁷R⁶⁸, wherein:

each of R⁶⁷ and R⁶⁸ is independently selected from the group consistingof H, C₁₋₆ alkyl, C₆₋₁₀ aryl, 5-to 10-membered heteroaryl, —C(O)R⁶⁹, and—C(O)NR⁷⁰R⁷¹, wherein the C₁₋₆alkyl is optionally substituted with oneor more substituents, and wherein the C₆₋₁₀ aryl and 5- to 10-memberedheteroaryl are optionally substituted with one or more substituents;R⁶⁹ is selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and5- to 10-membered heteroaryl, wherein the C₁₋₆alkyl is optionallysubstituted with one or more substituents, and wherein the C₆₋₁₀ aryland 5- to 10-membered heteroaryl are optionally substituted with one ormore substituents; andeach of R⁷⁰ and R⁷¹ is independently selected from the group consistingof H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, whereinthe C₁₋₆ alkyl is optionally substituted with one or more substituents,and wherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl areoptionally substituted with one or more substituents.

In some embodiments, R⁴ is —(C₆₋₁₀ arylene)-(C₁₋₆ alkylene)-NR⁶⁷R⁶⁸ or—C₁₋₆ alkylene-(C₆₋₁₀ arylene)-(C₁₋₆ alkylene)-NR⁶⁷R⁶⁸, wherein:

each of R⁶⁷ and R⁶⁸ is independently selected from the group consistingof H, C₁₋₆ alkyl, C₆₋₁₀ aryl, 5-to 10-membered heteroaryl, —C(O)R⁶⁹, and—C(O)NR⁷⁰R⁷¹, wherein the C₁₋₆alkyl is optionally substituted with oneor more substituents each independently selected from the groupconsisting of halogen, —OH, —NO₂, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, —NH₂,—NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)₂, —C₁₋₆ alkyl, haloC₁₋₆ alkyl, aminoC₁₋₆alkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, 5- to 10-memberedheterocycloalkyl, C₅₋₁₀ cycloalkyl, azido, —CN, —COR²⁰⁰ wherein R²⁰⁰ isC₁₋₆ alkyl or C₆₋₁₀ aryl, —CO₂R²⁰¹ wherein R²⁰¹ is H or C₁₋₆ alkyl,—CONR²⁰²R²⁰³ wherein R²⁰² and R²⁰³ is H or C₁₋₆ alkyl, —NR²⁰⁴COR²⁰⁵wherein R²⁰⁴ is H or C₁₋₆ alkyl and R²⁰⁵ is C₁₋₆ alkyl, —SO₂NR²⁰⁶R²⁰⁷wherein R²⁰⁶ and R²⁰⁷ is H or C₁₋₆ alkyl, and —NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸is H or C₁₋₆ alkyl and R²⁰⁹ is C₁₋₆ alkyl, and wherein the C₆₋₁₀ aryland 5- to 10-membered heteroaryl are optionally substituted with one ormore substituents each independently selected from the group consistingof halogen, —OH, —NO₂, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, —NH₂, —NH(C₁₋₆alkyl), —N(C₁₋₆ alkyl)₂, —C₁₋₆ alkyl, haloC₁₋₆ alkyl, aminoC₁₋₆ alkyl,C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, 5- to 10-memberedheterocycloalkyl, C₅₋₁₀ cycloalkyl, azido, —CN, —COR²⁰⁰ wherein R²⁰⁰ isC₁₋₆ alkyl or C₆₋₁₀ aryl, —CO₂R²⁰¹ wherein R²⁰¹ is H or C₁₋₆ alkyl,—CONR²⁰²R²⁰³ wherein R²⁰² and R²⁰³ is H or C₁₋₆ alkyl, —NR²⁰⁴COR²⁰⁵wherein R²⁰⁴ is H or C₁₋₆ alkyl and R²⁰⁵ is C₁₋₆ alkyl, —SO₂NR²⁰⁶R²⁰⁷wherein R²⁰⁶ and R²⁰⁷ is H or C₁₋₆ alkyl, and —NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸is H or C₁₋₆ alkyl and R²⁰⁹ is C₁₋₆ alkyl;R⁶⁹ is selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and5- to 10-membered heteroaryl, wherein the C₁₋₆alkyl is optionallysubstituted with one or more substituents each independently selectedfrom the group consisting of halogen, —OH, —NO₂, C₁₋₆alkoxy, C₁₋₆haloalkoxy, —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)₂, —C₁₋₆ alkyl,haloC₁₋₆ alkyl, aminoC₁₋₆ alkyl, C₆₋₁₀ aryl, 5- to 10-memberedheteroaryl, 5- to 10-membered heterocycloalkyl, C₅₋₁₀ cycloalkyl, azido,—CN, —COR²⁰⁰ wherein R²⁰⁰ is C₁₋₆ alkyl or C₆₋₁₀ aryl, —CO₂R²⁰¹ whereinR²⁰¹ is H or C₁₋₆ alkyl, —CONR²⁰²R²⁰³ wherein R²⁰² and R²⁰³ is H or C₁₋₆alkyl, —NR²⁰⁴COR²⁰⁵ wherein R²⁰⁴ is H or C₁₋₆ alkyl and R²⁰⁵ is C₁₋₆alkyl, —SO₂NR²⁰⁶R²⁰⁷ wherein R²⁰⁶ and R²⁰⁷ is H or C₁₋₆ alkyl, and—NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸ is H or C₁₋₆ alkyl and R²⁰⁹ is C₁₋₆ alkyl,and wherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl areoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, —OH, —NO₂, C₁₋₆alkoxy,C₁₋₆ haloalkoxy, —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)₂, —C₁₋₆ alkyl,haloC₁₋₆ alkyl, aminoC₁₋₆ alkyl, C₆₋₁₀ aryl, 5- to 10-memberedheteroaryl, 5- to 10-membered heterocycloalkyl, C₅₋₁₀ cycloalkyl, azido,—CN, —COR²⁰⁰ wherein R²⁰⁰ is C₁₋₆ alkyl or C₆₋₁₀ aryl, —CO₂R²⁰¹ whereinR²⁰¹ is H or C₁₋₆ alkyl, —CONR²⁰²R²⁰³ wherein R²⁰² and R²⁰³ is H or C₁₋₆alkyl, —NR²⁰⁴COR²⁰⁵ wherein R²⁰⁴ is H or C₁₋₆ alkyl and R²⁰⁵ is C₁₋₆alkyl, —SO₂NR²⁰⁶R²⁰⁷ wherein R²⁰⁶ and R²⁰⁷ is H or C₁₋₆ alkyl, and—NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸ is H or C₁₋₆ alkyl and R²⁰⁹ is C₁₋₆ alkyl;andeach of R⁷⁰ and R⁷¹ is independently selected from the group consistingof H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, whereinthe C₁₋₆ alkyl is optionally substituted with one or more substituentseach independently selected from the group consisting of halogen, —OH,—NO₂, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆alkyl)₂, —C₁₋₆ alkyl, haloC₁₋₆ alkyl, aminoC₁₋₆ alkyl, C₆₋₁₀ aryl, 5- to10-membered heteroaryl, 5- to 10-membered heterocycloalkyl, C₅₋₁₀cycloalkyl, azido, —CN, —COR²⁰⁰ wherein R²⁰⁰ is C₁₋₆ alkyl or C₆₋₁₀aryl, —CO₂R²⁰¹ wherein R²⁰¹ is H or C₁₋₆ alkyl, —CONR²⁰²R²⁰³ whereinR²⁰² and R²⁰³ is H or C₁₋₆ alkyl, —NR²⁰⁴COR²⁰⁵ wherein R²⁰⁴ is H or C₁₋₆alkyl and R²⁰⁵ is C₁₋₆ alkyl, —SO₂NR²⁰⁶R²⁰⁷ wherein R²⁰⁶ and R²⁰⁷ is Hor C₁₋₆ alkyl, and —NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸ is H or C₁₋₆ alkyl andR²⁰⁹ is C₁₋₆ alkyl, and wherein the C₆₋₁₀ aryl and 5- to 10-memberedheteroaryl are optionally substituted with one or more substituents eachindependently selected from the group consisting of halogen, —OH, —NO₂,C₁₋₆alkoxy, C₁₋₆ haloalkoxy, —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)₂,—C₁₋₆ alkyl, haloC₁₋₆ alkyl, aminoC₁₋₆ alkyl, C₆₋₁₀ aryl, 5- to10-membered heteroaryl, 5- to 10-membered heterocycloalkyl, C₅₋₁₀cycloalkyl, azido, —CN, —COR²⁰⁰ wherein R²⁰⁰ is C₁₋₆ alkyl or C₆₋₁₀aryl, —CO₂R²⁰¹ wherein R²⁰¹ is H or C₁₋₆ alkyl, —CONR²⁰²R²⁰³ whereinR²⁰² and R²⁰³ is H or C₁₋₆ alkyl, —NR²⁰⁴COR²⁰⁵ wherein R²⁰⁴ is H or C₁₋₆alkyl and R²⁰⁵ is C₁₋₆ alkyl, —SO₂NR²⁰⁶R²⁰⁷ wherein R²⁰⁶ and R²⁰⁷ is Hor C₁₋₆ alkyl, and —NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸ is H or C₁₋₆ alkyl andR²⁰⁹ is C₁₋₆ alkyl.

In some embodiments, R⁴ is —(C₆₋₁₀ arylene)-(C₁₋₆ alkylene)-NR⁶⁷R⁶⁸ or—C₁₋₆ alkylene-(C₆₋₁₀ arylene)-(C₁₋₆ alkylene)-NR⁶⁷R⁶⁸, wherein:

each of R⁶⁷ and R⁶⁸ is independently selected from the group consistingof H, C₁₋₆alkyl, C₆₋₁₀ aryl, 5-to 10-membered heteroaryl, —C(O)R⁶⁹, and—C(O)NR⁷⁰R⁷¹, wherein the C₁₋₆alkyl is optionally substituted with oneor more substituents each independently selected from the groupconsisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein the C₆₋₁₀aryl and 5- to 10-membered heteroaryl are optionally substituted withone or more substituents each independently selected from the groupconsisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy;R⁶⁹ is selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and5- to 10-membered heteroaryl, wherein the C₁₋₆alkyl is optionallysubstituted with one or more substituents each independently selectedfrom the group consisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy, andwherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionallysubstituted with one or more substituents each independently selectedfrom the group consisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy; andeach of R⁷⁰ and R^(7′) is independently selected from the groupconsisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl, wherein the C₁₋₆ alkyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen, —OH, —NO₂, and C₁₋₆ alkoxy, and wherein the C₆₋₁₀ aryl and5- to 10-membered heteroaryl are optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen, —OH, —NO₂, and C₁₋₆ alkoxy.

In some embodiments, R⁴ is —C₁ alkylene-(C₆ arylene)-(C₁alkylene)-NR⁶⁷R⁶⁸ and each of R⁶⁷ and R⁶⁸ is H. In other embodiments, R⁴is —C₁ alkylene-(C₆ arylene)-(C₁ alkylene)-NR⁶⁷R⁶⁸, R⁶⁷ is H, R⁶⁸ is—C(O)R⁶⁹, and R⁶⁹ is C₁ alkyl. In some embodiments, R⁴ is —C₁alkylene-(C₆ arylene)-(C₁ alkylene)-NR⁶⁷R⁶⁸, R⁶⁷ is H, R⁶⁸ is—C(O)NR⁷⁰R⁷¹, and each of R⁷⁰ and R⁷¹ is H.

In some embodiments, R⁴ is:

wherein:each of R¹³⁴ and R¹³⁵ is independently selected from the groupconsisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, 5-to 10-membered heteroaryl,—C(O)R¹³⁶, and —C(O)NR¹³⁷R¹³⁸, wherein the C₁₋₆alkyl is optionallysubstituted with one or more substituents each independently selectedfrom the group consisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy, andwherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionallysubstituted with one or more substituents each independently selectedfrom the group consisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy, andwherein n¹⁰ is 0, 1, 2, 3, or 4, and wherein n₁₁ is 0, 1, 2, 3, or 4;R¹³⁶ is selected from the group consisting of C₁₋₆ alkyl, C₆₋₁₀ aryl,and 5- to 10-membered heteroaryl, wherein the C₁₋₆alkyl is optionallysubstituted with one or more substituents each independently selectedfrom the group consisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy, andwherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionallysubstituted with one or more substituents each independently selectedfrom the group consisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy; andeach of R¹³⁷ and R¹³⁸ is independently selected from the groupconsisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl, wherein the C₁₋₆alkyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen, —OH, —NO₂, and C₁₋₆ alkoxy, and wherein the C₆₋₁₀ aryl and5- to 10-membered heteroaryl are optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen, —OH, —NO₂, and C₁₋₆ alkoxy.

In some embodiments, R⁴ is

wherein:each of R¹³⁹ and R¹⁴⁰ is independently selected from the groupconsisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, 5-to 10-membered heteroaryl,—C(O)R¹⁴¹, and —C(O)NR¹⁴²R¹⁴³, wherein the C₁₋₆alkyl is optionallysubstituted with one or more substituents each independently selectedfrom the group consisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy, andwherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionallysubstituted with one or more substituents each independently selectedfrom the group consisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy;R¹⁴¹ is selected from the group consisting of C₁₋₆ alkyl, C₆₋₁₀ aryl,and 5- to 10-membered heteroaryl, wherein the C₁₋₆alkyl is optionallysubstituted with one or more substituents each independently selectedfrom the group consisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy, andwherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionallysubstituted with one or more substituents each independently selectedfrom the group consisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy; andeach of R¹⁴² and R¹⁴³ is independently selected from the groupconsisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl, wherein the C₁₋₆alkyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen, —OH, —NO₂, and C₁₋₆ alkoxy, and wherein the C₆₋₁₀ aryl and5- to 10-membered heteroaryl are optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen, —OH, —NO₂, and C₁₋₆ alkoxy. In some embodiments, each of R¹³⁹and R¹⁴⁰ is independently selected from the group consisting of H,—C(O)R¹⁴¹, and —C(O)NR¹⁴²R¹⁴³, wherein R¹⁴¹ is C₁₋₆ alkyl and each ofR¹⁴² and R¹⁴³ is H.

In some embodiments, R⁴ is —(C₆₋₁₀ arylene)-NR⁷²R⁷³ or —C₁₋₆alkylene-(C₆₋₁₀ arylene)-NR⁷²R⁷³, wherein each of R⁷² and R⁷³ isindependently selected from the group consisting of H, C₁₋₆ alkyl, C₆₋₁₀aryl, and 5- to 10-membered heteroaryl, wherein the C₁₋₆alkyl isoptionally substituted with one or more substituents, and wherein theC₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally substitutedwith one or more substituents.

In some embodiments, R⁴ is —(C₆₋₁₀ arylene)-NR⁷²R⁷³ or —C₁₋₆alkylene-(C₆₋₁₀ arylene)-NR⁷²R⁷³, wherein each of R⁷² and R⁷³ isindependently selected from the group consisting of H, C₁₋₆ alkyl, C₆₋₁₀aryl, and 5- to 10-membered heteroaryl, wherein the C₁₋₆alkyl isoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, —OH, —NO₂, C₁₋₆alkoxy,C₁₋₆ haloalkoxy, —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)₂, —C₁₋₆ alkyl,haloC₁₋₆ alkyl, aminoC₁₋₆ alkyl, C₆₋₁₀ aryl, 5- to 10-memberedheteroaryl, 5- to 10-membered heterocycloalkyl, C₅₋₁₀ cycloalkyl, azido,—CN, —COR²⁰⁰ wherein R²⁰⁰ is C₁₋₆ alkyl or C₆₋₁₀ aryl, —CO₂R²⁰¹ whereinR²⁰¹ is H or C₁₋₆ alkyl, —CONR²⁰²R²⁰³ wherein R²⁰² and R²⁰³ is H or C₁₋₆alkyl, —NR²⁰⁴COR²⁰⁵ wherein R²⁰⁴ is H or C₁₋₆ alkyl and R²⁰⁵ is C₁₋₆alkyl, —SO₂NR²⁰⁶R²⁰⁷ wherein R²⁰⁶ and R²⁰⁷ is H or C₁₋₆ alkyl, and—NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸ is H or C₁₋₆ alkyl and R²⁰⁹ is C₁₋₆ alkyl,and wherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl areoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, —OH, —NO₂, C₁₋₆ alkoxy,C₁₋₆ haloalkoxy, —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)₂, —C₁₋₆ alkyl,haloC₁₋₆ alkyl, aminoC₁₋₆ alkyl, C₆₋₁₀ aryl, 5- to 10-memberedheteroaryl, 5- to 10-membered heterocycloalkyl, C₅₋₁₀ cycloalkyl, azido,—CN, —COR²⁰⁰ wherein R²⁰⁰ is C₁₋₆ alkyl or C₆₋₁₀ aryl, —CO₂R²⁰¹ whereinR²⁰¹ is H or C₁₋₆ alkyl, —CONR²⁰²R²⁰³ wherein R²⁰² and R²⁰³ is H or C₁₋₆alkyl, —NR²⁰⁴COR²⁰⁵ wherein R²⁰⁴ is H or C₁₋₆ alkyl and R²⁰⁵ is C₁₋₆alkyl, —SO₂NR²⁰⁶R²⁰⁷ wherein R²⁰⁶ and R²⁰⁷ is H or C₁₋₆ alkyl, and—NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸ is H or C₁₋₆ alkyl and R²⁰⁹ is C₁₋₆ alkyl.

In some embodiments, R⁴ is —C₁₋₂ alkylene-(C₆ arylene)-NR⁷²R⁷³ and eachof R⁷² and R⁷³ is independently selected from the group consisting of Hand C₁₋₆alkyl, wherein the C₁₋₆alkyl is optionally substituted with oneor more substituents each independently selected from the groupconsisting of 5- to 10-membered heterocycloalkyl, halogen, hydroxy,—NO₂, and C₁₋₆alkoxy. In other embodiments, R⁴ is —C₁₋₂ alkylene-(C₆arylene)-NR⁷²R⁷³ and R⁷² is H and R⁷³ is C₁₋₆alkyl optionallysubstituted with one or more substituents each independently selectedfrom the group consisting of 5- to 10-membered heterocycloalkyl,halogen, hydroxy, —NO₂, and C₁₋₆alkoxy. In some embodiments, R⁴ is —C₁₋₂alkylene-(C₆ arylene)-NR⁷²R⁷³ and R⁷² is H and R⁷³ is C₂ alkylsubstituted with morpholinyl. In some embodiments, R⁴ is —C₁₋₂alkylene-(C₆ arylene)-NR⁷²R⁷³ and R⁷² is H and R⁷³ is C₁₋₆ alkyl. Inother embodiments, R⁴ is —C₁₋₂ alkylene-(C₆ arylene)-NR⁷²R⁷³ and R⁷² isH and R⁷³ is C₅ alkyl.

In some embodiments, R⁴ is:

wherein each of R¹⁴⁴ and R¹⁴⁵ is independently selected from the groupconsisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl, wherein the C₁₋₆alkyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen, —OH, —NO₂, C₁₋₆alkoxy, and 5- to 10-memberedheterocycloalkyl, and wherein the C₆₋₁₀ aryl and 5- to 10-memberedheteroaryl are optionally substituted with one or more substituents eachindependently selected from the group consisting of halogen, —OH, —NO₂,C₁₋₆alkoxy, and 5- to 10-membered heterocycloalkyl, and wherein n¹² is0, 1, 2, 3, or 4. In some embodiments, n¹² is 1 or 2. In otherembodiments, n¹² is 1. In other embodiments, R¹⁴⁴ is H and R¹⁴⁵ isC₁₋₆alkyl optionally substituted with one or more substituents eachindependently selected from the group consisting of halogen, —OH, —NO₂,C₁₋₆alkoxy, and 5- to 10-membered heterocycloalkyl. In some embodiments,R¹⁴⁴ is H and R¹⁴⁵ is C₂ alkyl substituted with morpholinyl. In otherembodiments, R¹⁴⁴ is H and R¹⁴⁵ is C₁₋₆ alkyl. In other embodiments,R¹⁴⁴ is H and R¹⁴⁵ is C₅ alkyl.

In some embodiments, R⁴ is —(C₆₋₁₀ arylene)-OR⁷⁴ or —C₁₋₆alkylene-(C₆₋₁₀ arylene)-OR⁷⁴, wherein R⁷⁴ is selected from the groupconsisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl, wherein the C₁₋₆alkyl is optionally substituted with one ormore substituents, and wherein the C₆₋₁₀ aryl and 5- to 10-memberedheteroaryl are optionally substituted with one or more substituents. Inother embodiments, R⁴ is —(C₆₋₁₀ arylene)-OR⁷⁴ or —C₁₋₆ alkylene-(C₆₋₁₀arylene)-OR⁷⁴, wherein R⁷⁴ is selected from the group consisting ofC₂₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein theC₂₋₆alkyl is optionally substituted with one or more substituents, andwherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionallysubstituted with one or more substituents. In some embodiments, R⁴ is—(C₆₋₁₀ arylene)-OR⁷⁴ or —C₁₋₆ alkylene-(C₆₋₁₀ arylene)-OR⁷⁴, whereinR⁷⁴ is selected from the group consisting of C₃₋₆ alkyl, C₆₋₁₀ aryl, and5- to 10-membered heteroaryl, wherein the C₃₋₆ alkyl is optionallysubstituted with one or more substituents, and wherein the C₆₋₁₀ aryland 5- to 10-membered heteroaryl are optionally substituted with one ormore substituents.

In some embodiments, R⁴ is —(C₆₋₁₀ arylene)-OR⁷⁴ or —C₁₋₆alkylene-(C₆₋₁₀ arylene)-OR⁷⁴, wherein R⁷⁴ is selected from the groupconsisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl, wherein the C₁₋₆alkyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen, —OH, —NO₂, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, —NH₂, —NH(C₁₋₆alkyl), —N(C₁₋₆ alkyl)₂, —C₁₋₆ alkyl, haloC₁₋₆ alkyl, aminoC₁₋₆ alkyl,C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, 5- to 10-memberedheterocycloalkyl, C₅₋₁₀ cycloalkyl, azido, —CN, —COR²⁰⁰ wherein R²⁰⁰ isC₁₋₆ alkyl or C₆₋₁₀ aryl, —CO₂R²⁰¹ wherein R²⁰¹ is H or C₁₋₆ alkyl,—CONR²⁰²R²⁰³ wherein R²⁰² and R²⁰³ is H or C₁₋₆ alkyl, —NR²⁰⁴COR²⁰⁵wherein R²⁰⁴ is H or C₁₋₆ alkyl and R²⁰⁵ is C₁₋₆ alkyl, —SO₂NR²⁰⁶R²⁰⁷wherein R²⁰⁶ and R²⁰⁷ is H or C₁₋₆ alkyl, and —NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸is H or C₁₋₆ alkyl and R²⁰⁹ is C₁₋₆ alkyl, and wherein the C₆₋₁₀ aryland 5- to 10-membered heteroaryl are optionally substituted with one ormore substituents each independently selected from the group consistingof halogen, —OH, —NO₂, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, —NH₂, —NH(C₁₋₆alkyl), —N(C₁₋₆ alkyl)₂, —C₁₋₆ alkyl, haloC₁₋₆ alkyl, aminoC₁₋₆ alkyl,C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, 5- to 10-memberedheterocycloalkyl, C₅₋₁₀ cycloalkyl, azido, —CN, —COR²⁰⁰ wherein R²⁰⁰ isC₁₋₆ alkyl or C₆₋₁₀ aryl, —CO₂R²⁰¹ wherein R²⁰¹ is H or C₁₋₆ alkyl,—CONR²⁰²R²⁰³ wherein R²⁰² and R²⁰³ is H or C₁₋₆ alkyl, —NR²⁰⁴COR²⁰⁵wherein R²⁰⁴ is H or C₁₋₆ alkyl and R²⁰⁵ is C₁₋₆ alkyl, —SO₂NR²⁰⁶R²⁰⁷wherein R²⁰⁶ and R²⁰⁷ is H or C₁₋₆ alkyl, and —NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸is H or C₁₋₆ alkyl and R²⁰⁹ is C₁₋₆ alkyl.

In some embodiments, R⁴ is —(C₆₋₁₀ arylene)-OR⁷⁴ or —C₁₋₆alkylene-(C₆₋₁₀ arylene)-OR⁷⁴, wherein R⁷⁴ is selected from the groupconsisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl, wherein the C₁₋₆alkyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen, —OH, —NO₂, C₁₋₆alkoxy, and 5- to 10-memberedheterocycloalkyl, and wherein the C₆₋₁₀ aryl and 5- to 10-memberedheteroaryl are optionally substituted with one or more substituents eachindependently selected from the group consisting of halogen, —OH, —NO₂,C₁₋₆alkoxy, and 5- to 10-membered heterocycloalkyl. In otherembodiments, R⁴ is —(C₆₋₁₀ arylene)-OR⁷⁴ or —C₁₋₆ alkylene-(C₆₋₁₀arylene)-OR⁷⁴, wherein R⁷⁴ is selected from the group consisting ofC₂₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein theC₂₋₆alkyl is optionally substituted with one or more substituents eachindependently selected from the group consisting of halogen, —OH, —NO₂,C₁₋₆alkoxy, and 5- to 10-membered heterocycloalkyl, and wherein theC₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally substitutedwith one or more substituents each independently selected from the groupconsisting of halogen, —OH, —NO₂, C₁₋₆alkoxy, and 5- to 10-memberedheterocycloalkyl.

In some embodiments, R⁴ is —C₁₋₂ alkylene-(C₆ arylene)-OR⁷⁴ and R⁷⁴ isC₁₋₆alkyl optionally substituted with one or more substituents eachindependently selected from the group consisting of 5- to 10-memberedheterocycloalkyl, halogen, hydroxy, —NO₂, and C₁₋₆alkoxy. In someembodiments, R⁴ is —C₁₋₂ alkylene-(C₆ arylene)-OR⁷⁴ and R⁷⁴ is C₂₋₆alkyloptionally substituted with one or more substituents each independentlyselected from the group consisting of 5- to 10-memberedheterocycloalkyl, halogen, hydroxy, —NO₂, and C₁₋₆alkoxy. In someembodiments, R⁴ is-C₁₋₂ alkylene-(C₆ arylene)-OR⁷⁴ and R⁷⁴ is C₂₋₆alkyl.In other embodiments, R⁴ is —C₁₋₂ alkyene-(C₆ arylene)-OR⁷⁴ and R⁷⁴ isC₂ alkyl substituted with morpholinyl.

In some embodiments, R⁴ is:

wherein R¹⁴⁶ is selected from the group consisting of H, C₁₋₆ alkyl,C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the C₁₋₆ alkyl isoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, —OH, —NO₂, C₁₋₆alkoxy,and 5- to 10-membered heterocycloalkyl, and wherein the C₆₋₁₀ aryl and5- to 10-membered heteroaryl are optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen, —OH, —NO₂, C₁₋₆ alkoxy, and 5- to 10-membered heterocycloalkyl,and wherein n¹³ is 0, 1, 2, 3, or 4. In some embodiments, n¹³ is 1 or 2.In other embodiments, n¹³ is 1. In some embodiments, R¹⁴⁶ is selectedfrom the group consisting of C₂₋₆ alkyl, C₆₋₁₀ aryl, and 5- to10-membered heteroaryl, wherein the C₁₋₆ alkyl is optionally substitutedwith one or more substituents each independently selected from the groupconsisting of halogen, —OH, —NO₂, C₁₋₆ alkoxy, and 5- to 10-memberedheterocycloalkyl, and wherein the C₆₋₁₀ aryl and 5- to 10-memberedheteroaryl are optionally substituted with one or more substituents eachindependently selected from the group consisting of halogen, —OH, —NO₂,C₁₋₆alkoxy, and 5- to 10-membered heterocycloalkyl. In otherembodiments, R¹⁴⁶ is selected from the group consisting of C₂₋₆alkyl,C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl.

In some embodiments, R⁴ is

wherein R¹⁴⁷ is selected from the group consisting of H, C₁₋₆ alkyl,C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the C₁₋₆ alkyl isoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, —OH, —NO₂, C₁₋₆alkoxy,and 5- to 10-membered heterocycloalkyl, and wherein the C₆₋₁₀ aryl and5- to 10-membered heteroaryl are optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen, —OH, —NO₂, C₁₋₆ alkoxy, and 5- to 10-membered heterocycloalkyl.In other embodiments, R¹⁴⁷ is selected from the group consisting of C₂₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the C₂₋₆alkyl is optionally substituted with one or more substituents eachindependently selected from the group consisting of halogen, —OH, —NO₂,C₁₋₆alkoxy, and 5- to 10-membered heterocycloalkyl, and wherein theC₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally substitutedwith one or more substituents each independently selected from the groupconsisting of halogen, —OH, —NO₂, C₁₋₆ alkoxy, and 5- to 10-memberedheterocycloalkyl. In some embodiments, R¹⁴⁷ is selected from the groupconsisting of C₂₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl.In other embodiments, R¹⁴⁷ is C₂₋₆alkyl optionally substituted with oneor more substituents each independently selected from the groupconsisting of halogen, —OH, —NO₂, C₁₋₆ alkoxy, and 5- to 10-memberedheterocycloalkyl. In some embodiments, R¹⁴⁷ is C₂alkyl substituted withmorpholinyl. In other embodiments, R¹⁴⁷ is C₂alkyl.

In some embodiments, R⁴ is —C₁₋₆ alkylene-(C₆₋₁₀arylene)-N(R⁷⁵)—C(O)—CHR⁷⁶—NR⁷⁷R⁷⁸, wherein R⁷⁵ is H or CH₃, R⁷⁶ is H orC₁₋₆ alkyl optionally substituted with one or more substituents eachindependently selected from the group consisting of hydroxyl, —COOH,—NH₂, —C(O)NH₂, and —N(H)C(O)NH₂, and each of R⁷⁷ and R⁷⁸ isindependently H, CH₃ or acetyl.

In some embodiments, R⁴ is —C₁₋₆ alkylene-(C₆₋₁₀arylene)-N(R⁷⁵)—C(O)—CHR⁷⁶—N(H)R⁷⁸, wherein R⁷⁵ is H or CH₃, R⁷⁶ is H orC₁₋₆ alkyl optionally substituted with one or more substituents eachindependently selected from the group consisting of hydroxyl, —COOH,—NH₂, —C(O)NH₂, and —N(H)C(O)NH₂, and R⁷⁸ is H, CH₃ or acetyl.

In some embodiments, R⁴ is —C₁₋₂ alkylene-(C₆₋₁₀arylene)-N(R⁷⁵)—C(O)—CHR⁷⁶—N(H)R⁷⁸, R⁷⁵ is H, R⁷⁶ is H, and R⁷⁸ is H oracetyl. In other embodiments, R⁴ is —C₁₋₂ alkylene-(C₆₋₁₀arylene)-N(R⁷⁵)—C(O)—CHR⁷⁶—N(H)R⁷⁸, R⁷⁵ is H, R⁷⁶ is H, and R⁷⁸ is H. Insome embodiments, R⁴ is —C₁₋₂ alkylene-(C₆₋₁₀arylene)-N(R⁷⁵)—C(O)—CHR⁷⁶—N(H)R⁷⁸, R⁷⁵ is H, R⁷⁶ is H, and R⁷⁸ isacetyl.

In some embodiments, R⁴ is —C₁₋₂ alkylene-(C₆₋₁₀arylene)-N(R⁷⁵)—C(O)—CHR⁷⁶—N(H)R⁷⁸, R⁷⁵ is H, R⁷⁶ is C₁₋₆alkyloptionally substituted with one or more substituents each independentlyselected from the group consisting of hydroxyl, —COOH, —NH₂, —C(O)NH₂,and —N(H)C(O)NH₂, and R⁷⁸ is H.

In some embodiments, R⁴ is —C₁₋₂ alkylene-(C₆₋₁₀arylene)-N(R⁷⁵)—C(O)—CHR⁷⁶—N(H)R⁷⁸, R⁷⁵ is H, R⁷⁶ is C₁₋₆alkylsubstituted with hydroxyl, and R⁷⁸ is H. In some embodiments, R⁴ is—C₁₋₂ alkylene-(C₆₋₁₀ arylene)-N(R⁷⁵)—C(O)—CHR⁷⁶—N(H)R⁷⁸, R⁷⁵ is H, R⁷⁶is C₁₋₆alkyl substituted with —COOH, and R⁷⁸ is H. In some embodiments,R⁴ is —C₁₋₂ alkylene-(C₆₋₁₀ arylene)-N(R⁷⁵)—C(O)—CHR⁷⁶—N(H)R⁷⁸, R⁷⁵ isH, R⁷⁶ is C₁₋₆alkyl substituted with —NH₂, and R⁷⁸ is H. In someembodiments, R⁴ is —C₁₋₂ alkylene-(C₆₋₁₀arylene)-N(R⁷⁵)—C(O)—CHR⁷⁶—N(H)R⁷⁸, R⁷⁵ is H, R⁷⁶ is C₁₋₆alkylsubstituted with —C(O)NH₂, and R⁷⁸ is H. In some embodiments, R⁴ is—C₁₋₂ alkylene-(C₆₋₁₀ arylene)-N(R⁷⁵)—C(O)—CHR⁷⁶—N(H)R⁷⁸, R^(7′) is H,R⁷⁶ is C₁₋₆ alkyl substituted with —N(H)C(O)NH₂, and R⁷⁸ is H.

In some embodiments, R⁴ is:

wherein R¹⁴⁸ is H or CH₃, R¹⁴⁹ is H or C₁₋₆alkyl optionally substitutedwith one or more substituents each independently selected from the groupconsisting of hydroxyl, —COOH, —NH₂, —C(O)NH₂, and —N(H)C(O)NH₂, andR¹⁵⁰ is H, CH₃ or acetyl, and wherein n¹⁴ is 0, 1, 2, 3, or 4. In otherembodiments, n¹⁴ is 1 or 2. In some embodiments, n¹⁴ is 1. In someembodiments, R¹⁴⁸ is H, R¹⁴⁹ is H, and R¹⁵⁰ is H or acetyl. In otherembodiments, R¹⁴⁸ is H, R¹⁴⁹ is H, and R¹⁵⁰ is H. In some embodiments,R¹⁴⁸ is H, R¹⁴⁹ is H, and R¹⁵⁰ is acetyl. In some embodiments, R¹⁴⁸ isH, R¹⁴⁹ is C₁₋₆alkyl optionally substituted with one or moresubstituents each independently selected from the group consisting ofhydroxyl, —COOH, —NH₂, —C(O)NH₂, and —N(H)C(O)NH₂, and R¹⁵⁰ is H. Insome embodiments, R¹⁴⁸ is H, R¹⁴⁹ is C₁₋₆alkyl substituted withhydroxyl, and R¹⁵⁰ is H. In some embodiments, R¹⁴⁸ is H, R¹⁴⁹ is C₁₋₆alkyl substituted with —COOH, and R¹⁵⁰ is H. In some embodiments, R¹⁴⁸is H, R¹⁴⁹ is C₁₋₆ alkyl substituted with —NH₂, and R¹⁵⁰ is H. In someembodiments, R¹⁴⁸ is H, R¹⁴⁹ is C₁₋₆ alkyl substituted with —C(O)NH₂,and R¹⁵⁰ is H. In some embodiments, R¹⁴⁸ is H, R¹⁴⁹ is C₁₋₆alkylsubstituted with —N(H)C(O)NH₂, and R¹⁵⁰ is H.

In some embodiments, R⁴ is —C₁₋₆ alkylene-(C₆₋₁₀ arylene)-CN. In otherembodiments, R⁴ is —C₁₋₂ alkylene-(C₆ arylene)-CN. In other embodiments,R⁴ is —C₁ alkylene-(C₆ arylene)-CN. In some embodiments, R⁴ is

wherein n¹⁵ is 0, 1, 2, 3, or 4. In other embodiments, n¹⁵ is 1 or 2. Insome embodiments, R⁴ is

In some embodiments, R⁴ is selected from the group consisting of:

In some embodiments, R is selected from the group consisting of:

In some embodiments R⁴ is selected from the group consisting of:

In some embodiments R⁴ is selected from the group consisting of:

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

In some embodiments, R⁴ is

Embodiments of R⁵ and n¹

In some embodiments, R⁵ is selected from the group consisting of:

-   -   (i) —NR⁷⁹R⁸⁰, wherein each of R⁷⁹ and R⁸⁰ is independently        selected from the group consisting of H, C₁₋₆ alkyl, —C(O)R⁸¹,        and —C(═NR⁸²)NR⁸³R⁸⁴, or R⁷⁹ and R⁸⁰, together with the N atom        to which they are attached, form 5- to 10-membered heteroaryl or        5- to 10-membered heterocycloalkyl, wherein the C₁₋₆ alkyl is        optionally substituted with one or more substituents, and        wherein the 5- to 10-membered heteroaryl and 5- to 10-membered        heterocycloalkyl are optionally substituted with one or more        substituents,        -   R⁸¹ is selected from the group consisting of H, —NH₂, C₁₋₁₆            alkyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, and 5- to 10-membered            heteroaryl; and        -   each of R⁸², R⁸³, and R⁸⁴ is independently selected from the            group consisting of H, C₁₋₁₆₋alkyl, C₁₋₆ haloalkyl, C₆₋₁₀            aryl, and 5- to 10-membered heteroaryl; and    -   (ii) —N+R⁸⁵R⁸⁶R⁸⁷, wherein each of R⁸⁵, R⁸⁶, and R⁸⁷ is        independently C₁₋₆ alkyl.

In some embodiments, R⁵ is selected from the group consisting of:

-   -   (i) —NR⁷⁹R⁸⁰, wherein each of R⁷⁹ and R⁸⁰ is independently        selected from the group consisting of H, C₁₋₆ alkyl, —C(O)R⁸¹,        and —C(═NR⁸²)NR⁸³R⁸⁴, or R⁷⁹ and R⁸⁰, together with the N atom        to which they are attached, form 5- to 10-membered heteroaryl or        5- to 10-membered heterocycloalkyl, wherein the C₁₋₆ alkyl is        optionally substituted with one or more substituents each        independently selected from the group consisting of halogen,        —OH, —NO₂, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, —NH₂, —NH(C₁₋₆ alkyl),        —N(C₁₋₆ alkyl)₂, —C₁₋₆ alkyl, haloC₁₋₆ alkyl, aminoC₁₋₆ alkyl,        C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, 5- to 10-membered        heterocycloalkyl, C₅₋₁₀ cycloalkyl, azido, —CN, —COR²⁰⁰ wherein        R²⁰⁰ is C₁₋₆ alkyl or C₆₋₁₀ aryl, —CO₂R²⁰¹ wherein R²⁰¹ is H or        C₁₋₆ alkyl, —CONR²⁰²R²⁰³ wherein R²⁰² and R²⁰³ is H or C₁₋₆        alkyl, —NR²⁰⁴COR²⁰⁵ wherein R²⁰⁴ is H or C₁₋₆ alkyl and R²⁰⁵ is        C₁₋₆ alkyl, —SO₂NR²⁰⁶R²⁰⁷ wherein R²⁰⁶ and R²⁰⁷ is H or C₁₋₆        alkyl, and —NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸ is H or C₁₋₆ alkyl and        R²⁰⁹ is C₁₋₆ alkyl, and wherein the 5- to 10-membered heteroaryl        and 5- to 10-membered heterocycloalkyl are optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂,        C₁₋₆alkoxy, C₁₋₆ haloalkoxy, —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆        alkyl)₂, —C₁₋₆ alkyl, haloC₁₋₆ alkyl, aminoC₁₋₆ alkyl, C₆₋₁₀        aryl, 5- to 10-membered heteroaryl, 5- to 10-membered        heterocycloalkyl, C₅₋₁₀ cycloalkyl, azido, —CN, —COR²⁰⁰ wherein        R²⁰⁰ is C₁₋₆ alkyl or C₆₋₁₀ aryl, —CO₂R²⁰¹ wherein R²⁰¹ is H or        C₁₋₆ alkyl, —CONR²⁰²R²⁰³ wherein R²⁰² and R²⁰³ is H or C₁₋₆        alkyl, —NR²⁰⁴COR²⁰⁵ wherein R²⁰⁴ is H or C₁₋₆ alkyl and R²⁰⁵ is        C₁₋₆ alkyl, —SO₂NR²⁰⁶R²⁰⁷ wherein R²⁰⁶ and R²⁰⁷ is H or C₁₋₆        alkyl, and —NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸ is H or C₁₋₆ alkyl and        R²⁰⁹ is C₁₋₆ alkyl,        -   R⁸¹ is selected from the group consisting of H, —NH₂, C₁₋₁₆            alkyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, and 5- to 10-membered            heteroaryl; and        -   each of R⁸², R⁸³, and R⁸⁴ is independently selected from the            group consisting of H, C₁₋₁₆ alkyl, C₁₋₆ haloalkyl, C₆₋₁₀            aryl, and 5- to 10-membered heteroaryl; and    -   (ii) —N⁺R⁸⁵R⁸⁶R⁸⁷, wherein each of R⁸⁵, R⁸⁶, and R⁸⁷ is        independently C₁₋₆ alkyl.

In other embodiments, R⁵ is —NR⁷⁹R⁸⁰, wherein:

-   -   each of R⁷⁹ and R⁸⁰ is independently selected from the group        consisting of H, C₁₋₆alkyl, —C(O)R⁸¹, and —C(═NR⁸²)NR⁸³R⁸⁴, or        R⁷⁹ and R⁸⁰, together with the N atom to which they are        attached, form 5- to 10-membered heteroaryl or 5- to 10-membered        heterocycloalkyl, wherein the C₁₋₆alkyl is optionally        substituted with one or more substituents, and wherein the 5- to        10-membered heteroaryl and 5- to 10-membered heterocycloalkyl        are optionally substituted with one or more substituents, R⁸¹ is        selected from the group consisting of H, —NH₂, C₁₋₁₆ alkyl, C₁₋₆        haloalkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl; and        each of R⁸², R⁸³, and R⁸⁴ is independently selected from the        group consisting of H, C₁₋₁₆ alkyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl,        and 5- to 10-membered heteroaryl.

In other embodiments, R⁵ is —NR⁷⁹R⁸⁰, wherein:

-   -   each of R⁷⁹ and R⁸⁰ is independently selected from the group        consisting of H, C₁₋₆alkyl, —C(O)R⁸¹, and —C(═NR⁸²)NR⁸³R⁸⁴, or        R⁷⁹ and R⁸⁰, together with the N atom to which they are        attached, form 5- to 10-membered heteroaryl or 5- to 10-membered        heterocycloalkyl, wherein the C₁₋₆alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂,        C₁₋₆alkoxy, C₁₋₆ haloalkoxy, —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆        alkyl)₂, —C₁₋₆ alkyl, haloC₁₋₆ alkyl, aminoC₁₋₆ alkyl, C₆₋₁₀        aryl, 5- to 10-membered heteroaryl, 5- to 10-membered        heterocycloalkyl, C₅₋₁₀ cycloalkyl, azido, —CN, —COR²⁰⁰ wherein        R²⁰⁰ is C₁₋₆ alkyl or C₆₋₁₀ aryl, —CO₂R²⁰¹ wherein R²⁰¹ is H or        C₁₋₆ alkyl, —CONR²⁰²R²⁰³ wherein R²⁰² and R²⁰³ is H or C₁₋₆        alkyl, —NR²⁰⁴COR²⁰⁵ wherein R²⁰⁴ is H or C₁₋₆ alkyl and R²⁰⁵ is        C₁₋₆ alkyl, —SO₂NR²⁰⁶R²⁰⁷ wherein R²⁰⁶ and R²⁰⁷ is H or C₁₋₆        alkyl, and —NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸ is H or C₁₋₆ alkyl and        R²⁰⁹ is C₁₋₆ alkyl, and wherein the 5- to 10-membered heteroaryl        and 5- to 10-membered heterocycloalkyl are optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, C₁₋₆        alkoxy, C₁₋₆ haloalkoxy, —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)₂,        —C₁₋₆ alkyl, haloC₁₋₆ alkyl, aminoC₁₋₆ alkyl, C₆₋₁₀ aryl, 5- to        10-membered heteroaryl, 5- to 10-membered heterocycloalkyl,        C₅₋₁₀ cycloalkyl, azido, —CN, —COR²⁰⁰ wherein R²⁰⁰ is C₁₋₆ alkyl        or C₆₋₁₀ aryl, —CO₂R²⁰¹ wherein R²⁰¹ is H or C₁₋₆ alkyl,        —CONR²⁰²R²⁰³ wherein R²⁰² and R²⁰³ is H or C₁₋₆ alkyl,        —NR²⁰⁴COR²⁰⁵ wherein R²⁰⁴ is H or C₁₋₆ alkyl and R²⁰⁵ is C₁₋₆        alkyl, —SO₂NR²⁰⁶R²⁰⁷ wherein R²⁰⁶ and R²⁰⁷ is H or C₁₋₆ alkyl,        and —NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸ is H or C₁₋₆ alkyl and R²⁰⁹ is        C₁₋₆ alkyl, R⁸¹ is selected from the group consisting of H,        —NH₂, C₁₋₁₆ alkyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl; and    -   each of R⁸², R⁸³, and R⁸⁴ is independently selected from the        group consisting of H, C₁₋₁₆ alkyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl,        and 5- to 10-membered heteroaryl.

In other embodiments, R⁵ is —NR⁷⁹R⁸⁰, wherein each of R⁷⁹ and R⁸⁰ isindependently selected from the group consisting of H and C₁₋₆alkyl,wherein the C₁₋₆alkyl is optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen, —OH, —NO₂, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, —NH₂, —NH(C₁₋₆ alkyl),—N(C₁₋₆ alkyl)₂, —C₁₋₆ alkyl, haloC₁₋₆ alkyl, aminoC₁₋₆ alkyl, C₆₋₁₀aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocycloalkyl,C₅₋₁₀ cycloalkyl, azido, —CN, —COR²⁰⁰ wherein R²⁰⁰ is C₁₋₆ alkyl orC₆₋₁₀ aryl, —CO₂R²⁰¹ wherein R²⁰¹ is H or C₁₋₆ alkyl, —CONR²⁰²R²⁰³wherein R²⁰² and R²⁰³ is H or C₁₋₆ alkyl, —NR²⁰⁴COR²⁰⁵ wherein R²⁰⁴ is Hor C₁₋₆ alkyl and R²⁰⁵ is C₁₋₆ alkyl, —SO₂NR²⁰⁶R²⁰⁷ wherein R²⁰⁶ andR²⁰⁷ is H or C₁₋₆ alkyl, and —NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸ is H or C₁₋₆alkyl and R²⁰⁹ is C₁₋₆ alkyl. In other embodiments, R⁵ is —NR⁷⁹R⁸⁰,wherein each of R⁷⁹ and R⁸⁰ is H. In other embodiments, R⁵ is —NR⁷⁹R⁸⁰,wherein each of R⁷⁹ and R⁸⁰ is independently C₁₋₆ alkyl. In otherembodiments, R⁵ is —NR⁷⁹R⁸⁰, wherein each of R⁷⁹ and R⁸⁰ isindependently C₁₋₃ alkyl. In other embodiments, R⁵ is —NR⁷⁹R⁸⁰, whereineach of R⁷⁹ and R⁸⁰ is CH₃. In other embodiments, R⁵ is —NR⁷⁹R⁸⁰,wherein R⁷⁹ is H and R⁸⁰ is C₁₋₆ alkyl. In other embodiments, R⁵ is—NR⁷⁹R⁸⁰, wherein R⁷⁹ is H and R⁸⁰ is C₁₋₃ alkyl. In other embodiments,R⁵ is —NR⁷⁹R⁸⁰, wherein R⁷⁹ is H and R⁸⁰ is CH₃.

In other embodiments, R⁵ is —NR⁷⁹R⁸⁰, wherein each of R⁷⁹ and R⁸⁰ isindependently selected from the group consisting of H and —C(O)R⁸¹,wherein R⁸¹ is selected from the group consisting of H, —NH₂, C₁₋₁₆alkyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl. Inother embodiments, R⁵ is —NR⁷⁹R⁸⁰, wherein each of R⁷⁹ and R⁸⁰ isindependently selected from the group consisting of H and—C(═NR⁸²)NR⁸³R⁸⁴, wherein each of R⁸², R⁸³, and R⁸⁴ is independentlyselected from the group consisting of H, C₁₋₁₆ alkyl, C₁₋₆ haloalkyl,C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl. In some embodiments, R⁵ is—NR⁷⁹R⁸⁰ and each of R⁷⁹ and R⁸⁰ is independently selected from thegroup consisting of H, C₁₋₆ alkyl, —C(O)R⁸¹, and —C(═NR⁸²)NR⁸³R⁸⁴,wherein R⁸¹ is C₁₋₆ alkyl and each of R⁸², R⁸³, and R⁸⁴ is H. In otherembodiments, R⁵ is —NR⁷⁹R⁸⁰ and each of R⁷⁹ and R⁸⁰ is independentlyselected from the group consisting of H and C₁₋₆ alkyl. In someembodiments, R⁵ is —NH₂, —NHCH₃ or —N(CH₃)₂. In other embodiments, R⁵ is—NH₂. In some embodiments, R⁵ is —NHCH₃. In other embodiments, R⁵ is—N(CH₃)₂. In other embodiments, R⁵ is —NR⁷⁹R⁸⁰, wherein R⁷⁹ and R⁸⁰,together with the N atom to which they are attached, form 5- to10-membered heteroaryl or 5- to 10-membered heterocycloalkyl, whereinthe 5- to 10-membered heteroaryl and 5- to 10-membered heterocycloalkylare optionally substituted with one or more substituents eachindependently selected from the group consisting of halogen, —OH, —NO₂,C₁₋₆alkoxy, C₁₋₆ haloalkoxy, —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)₂,—C₁₋₆ alkyl, haloC₁₋₆ alkyl, aminoC₁₋₆ alkyl, C₆₋₁₀ aryl, 5- to10-membered heteroaryl, 5- to 10-membered heterocycloalkyl, C₅₋₁₀cycloalkyl, azido, —CN, —COR²⁰⁰ wherein R²⁰⁰ is C₁₋₆ alkyl or C₆₋₁₀aryl, —CO₂R²⁰¹ wherein R²⁰¹ is H or C₁₋₆ alkyl, —CONR²⁰²R²⁰³ whereinR²⁰² and R²⁰³ is H or C₁₋₆ alkyl, —NR²⁰⁴COR²⁰⁵ wherein R²⁰⁴ is H or C₁₋₆alkyl and R²⁰⁵ is C₁₋₆ alkyl, —SO₂NR²⁰⁶R²⁰⁷ wherein R²⁰⁶ and R²⁰⁷ is Hor C₁₋₆ alkyl, and —NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸ is H or C₁₋₆ alkyl andR²⁰⁹ is C₁₋₆ alkyl. In some embodiments, R⁵ is —N⁺R⁸⁵R⁸⁶R⁸⁷, whereineach of R⁸⁵, R⁸⁶, and R⁸⁷ is independently C₁₋₆ alkyl. In otherembodiments, each of R⁸⁵, R⁸⁶, and R⁸⁷ is independently C₁₋₃ alkyl. Inother embodiments, each of R⁸⁵, R⁸⁶, and R⁸⁷ is CH₃. In someembodiments, n¹ is 1, 2, 3, 4, 5, or 6. In some embodiments, n¹ is 2, 3,4, 5, or 6. In some embodiments, n¹ is 2, 3, 4, or 5. In someembodiments, n¹ is 3, 4, or 5. In some embodiments, n¹ is 3 or 4. Insome embodiments, n¹ is 1. In some embodiments, n¹ is 2. In someembodiments, n¹ is 3. In some embodiments, n¹ is 4. In some embodiments,n¹ is 5. In some embodiments, n¹ is 6.

Embodiments of R⁶

In some embodiments, R⁶ is alkyl optionally substituted with one or moresubstituents. In other embodiments, R⁶ is C₁₋₆ alkyl optionallysubstituted with one or more substituents. In some embodiments, R⁶ isC₁₋₆ alkyl optionally substituted with one or more substituents eachindependently selected from the group consisting of halogen, hydroxy,—NO₂, and C₁₋₆ alkoxy. In some embodiments, R⁶ is C₁₋₆ alkyl optionallysubstituted with hydroxy. In other embodiments, R⁶ is C₁₋₅ alkyloptionally substituted with hydroxy. In some embodiments, R⁶ is C₁₋₄alkyl optionally substituted with hydroxy. In some embodiments, R⁶ isC₁₋₃ alkyl optionally substituted with hydroxy.

In some embodiments, R⁶ is C₁₋₂ alkyl optionally substituted withhydroxy. In some embodiments, R⁶ is selected from the group consistingof —CH₂CH₂CH₂CH₃, —CH(CH₃)CH₂CH₃, —CH₂CH(CH₃)₂, —CH₂CH₂CH₃,—CH(CH₃)CH₂OH, —CH(CH₃)₂, —C(CH₃)₃, —CH(CH₃)OH, and —CH₂CH₃. In otherembodiments, R⁶ is selected from the group consisting of —CH(CH₃)OH,—CH(CH₃)₂, —C(CH₃)₃, —CH₂OH and —CH₂CH₃. In some embodiments, R⁶ isselected from the group consisting of —CH(CH₃)OH, —CH(CH₃)₂, —C(CH₃)₃,and —CH₂CH₃. In some embodiments, R⁶ is —CH(CH₃)OH. In some embodiments,R⁶ is —CH(CH₃)₂. In some embodiments, R⁶ is —C(CH₃)₃. In someembodiments, R⁶ is —CH₂CH₃. In some embodiments, R⁶ is —CH₂OH.

Embodiments of R⁸

In some embodiments, R⁸ is selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, —C₁₋₆ alkylene(C₆₋₁₀aryl) and —C₁₋₆alkylene(5- to 10-membered heteroaryl), wherein the C₁₋₆alkyl, the C₆₋₁₀ aryl, the C₆₋₁₀ aryl of —C₁₋₆ alkylene(C₆₋₁₀ aryl), the5- to 10-membered heteroaryl and the 5-to 10-membered heteroaryl of—C₁₋₆alkylene(5- to 10-membered heteroaryl) are optionally substitutedwith one or more substituents, and wherein the C₁₋₆alkylene of—C₁₋₆alkylene(C₆₋₁₀ aryl) and —C₁₋₆alkylene(5- to 10-memberedheteroaryl) is optionally substituted with one or more substituents.

In some embodiments, R⁸ is selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, —C₁— alkylene(C₆₋₁₀aryl) and —C₁₋₆alkylene(5- to 10-membered heteroaryl), wherein the C₁₋₆alkyl, the C₆₋₁₀ aryl, the C₆₋₁₀ aryl of —C₁₋₆ alkylene(C₆₋₁₀ aryl), the5- to 10-membered heteroaryl and the 5-to 10-membered heteroaryl of—C₁₋₆alkylene(5- to 10-membered heteroaryl) are optionally substitutedwith one or more substituents each independently selected from the groupconsisting of halogen, —OH, —NO₂, C₁₋₆alkoxy, C₁₋₆ haloalkoxy, —NH₂,—NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)₂, —C₁₋₆ alkyl, haloC₁₋₆ alkyl, aminoC₁₋₆alkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, 5- to 10-memberedheterocycloalkyl, C₅₋₁₀ cycloalkyl, azido, —CN, —COR²⁰⁰ wherein R²⁰⁰ isC₁₋₆ alkyl or C₆₋₁₀ aryl, —CO₂R²⁰¹ wherein R²⁰¹ is H or C₁₋₆ alkyl,—CONR²⁰²R²⁰³ wherein R²⁰² and R²⁰³ is H or C₁₋₆ alkyl, —NR²⁰⁴COR²⁰⁵wherein R²⁰⁴ is H or C₁₋₆ alkyl and R²⁰⁵ is C₁₋₆ alkyl, —SO₂NR²⁰⁶R²⁰⁷wherein R²⁰⁶ and R²⁰⁷ is H or C₁₋₆ alkyl, and —NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸is H or C₁₋₆ alkyl and R²⁰⁹ is C₁₋₆ alkyl, and wherein the C₁₋₆alkyleneof —C₁₋₆alkylene(C₆₋₁₀ aryl) and —C₁₋₆ alkylene(5- to 10-memberedheteroaryl) is optionally substituted with one or more substituents eachindependently selected from the group consisting of halogen, —OH, —NO₂,C₁₋₆alkoxy, C₁₋₆ haloalkoxy, —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)₂,—C₁₋₆ alkyl, haloC₁₋₆ alkyl, aminoC₁₋₆ alkyl, C₆₋₁₀ aryl, 5- to10-membered heteroaryl, 5- to 10-membered heterocycloalkyl, C₅₋₁₀cycloalkyl, azido, —CN, —COR²⁰⁰ wherein R²⁰⁰ is C₁₋₆ alkyl or C₆₋₁₀aryl, —CO₂R²⁰¹ wherein R²⁰¹ is H or C₁₋₆ alkyl, —CONR²⁰²R²⁰³ whereinR²⁰² and R²⁰³ is H or C₁₋₆ alkyl, —NR²⁰⁴COR²⁰⁵ wherein R²⁰⁴ is H or C₁₋₆alkyl and R²⁰⁵ is C₁₋₆ alkyl, —SO₂NR²⁰⁶R²⁰⁷ wherein R²⁰⁶ and R²⁰⁷ is Hor C₁₋₆ alkyl, and —NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸ is H or C₁₋₆ alkyl andR²⁰⁹ is C₁₋₆ alkyl.

In some embodiments, R⁸ is selected from the group consisting ofC₁₋₆alkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, —C₁₋₆alkylene(C₆₋₁₀aryl) and —C₁₋₆alkylene(5- to 10-membered heteroaryl), wherein theC₁₋₆alkyl, the C₆₋₁₀ aryl, the C₆₋₁₀ aryl of —C₁₋₆alkylene(C₆₋₁₀ aryl),the 5- to 10-membered heteroaryl and the 5-to 10-membered heteroaryl of—C₁₋₆alkylene(5- to 10-membered heteroaryl) are optionally substitutedwith one or more substituents each independently selected from the groupconsisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein theC₁₋₆alkylene of —C₁₋₆alkylene(C₆₋₁₀ aryl) and —C₁₋₆alkylene(5- to10-membered heteroaryl) is optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen, —OH, —NO₂, C₁₋₆alkoxy, and C₆₋₁₀ aryl.

In some embodiments, R⁸ is selected from the group consisting of C₆₋₁₀aryl, 5- to 10-membered heteroaryl, —C₁₋₆alkylene(C₆₋₁₀ aryl) and—C₁₋₆alkylene(5- to 10-membered heteroaryl), wherein the C₆₋₁₀ aryl andthe C₆₋₁₀ aryl of —C₁₋₆alkylene(C₆₋₁₀ aryl) and the 5- to 10-memberedheteroaryl and the 5- to 10-membered heteroaryl of —C₁₋₆alkylene(5- to10-membered heteroaryl) are optionally substituted with one or moresubstituents, and wherein the C₁₋₆alkylene of —C₁₋₆ alkylene(C₆₋₁₀ aryl)and —C₁₋₆alkylene(5- to 10-membered heteroaryl) is optionallysubstituted with one or more substituents.

In some embodiments, R⁸ is selected from the group consisting of C₆₋₁₀aryl, 5- to 10-membered heteroaryl, —C₁₋₆alkylene(C₆₋₁₀ aryl) and—C₁₋₆alkylene(5- to 10-membered heteroaryl), wherein the C₆₋₁₀ aryl andthe C₆₋₁₀ aryl of —C₁₋₆alkylene(C₆₋₁₀ aryl) and the 5- to 10-memberedheteroaryl and the 5- to 10-membered heteroaryl of —C₁₋₆ alkylene(5- to10-membered heteroaryl) are optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen, —OH, —NO₂, C₁₋₆ alkoxy, C₁₋₆ haloalkoxy, —NH₂, —NH(C₁₋₆ alkyl),—N(C₁₋₆ alkyl)₂, —C₁₋₆ alkyl, haloC₁₋₆ alkyl, aminoC₁₋₆ alkyl, C₆₋₁₀aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heterocycloalkyl,C₅₋₁₀ cycloalkyl, azido, —CN, —COR²⁰⁰ wherein R²⁰⁰ is C₁₋₆ alkyl orC₆₋₁₀ aryl, —CO₂R²⁰¹ wherein R²⁰¹ is H or C₁₋₆ alkyl, —CONR²⁰²R²⁰³wherein R²⁰² and R²⁰³ is H or C₁₋₆ alkyl, —NR²⁰⁴COR²⁰⁵ wherein R²⁰⁴ is Hor C₁₋₆ alkyl and R²⁰⁵ is C₁₋₆ alkyl, —SO₂NR²⁰⁶R²⁰⁷ wherein R²⁰⁶ andR²⁰⁷ is H or C₁₋₆ alkyl, and —NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸ is H or C₁₋₆alkyl and R²⁰⁹ is C₁₋₆ alkyl, and wherein the C₁₋₆alkylene of—C₁₋₆alkylene(C₆₋₁₀ aryl) and —C₁₋₆ alkylene(5- to 10-memberedheteroaryl) is optionally substituted with one or more substituents eachindependently selected from the group consisting of halogen, —OH, —NO₂,C₁₋₆alkoxy, C₁₋₆ haloalkoxy, —NH₂, —NH(C₁₋₆ alkyl), —N(C₁₋₆ alkyl)₂,—C₁₋₆ alkyl, haloC₁₋₆ alkyl, aminoC₁₋₆ alkyl, C₆₋₁₀ aryl, 5- to10-membered heteroaryl, 5- to 10-membered heterocycloalkyl, C₅₋₁₀cycloalkyl, azido, —CN, —COR²⁰⁰ wherein R²⁰⁰ is C₁₋₆ alkyl or C₆₋₁₀aryl, —CO₂R²⁰¹ wherein R²⁰¹ is H or C₁₋₆ alkyl, —CONR²⁰²R²⁰³ whereinR²⁰² and R²⁰³ is H or C₁₋₆ alkyl, —NR²⁰⁴COR²⁰⁵ wherein R²⁰⁴ is H or C₁₋₆alkyl and R²⁰⁵ is C₁₋₆ alkyl, —SO₂NR²⁰⁶R²⁰⁷ wherein R²⁰⁶ and R²⁰⁷ is Hor C₁₋₆ alkyl, and —NR²⁰⁸SO₂R²⁰⁹ wherein R²⁰⁸ is H or C₁₋₆ alkyl andR²⁰⁹ is C₁₋₆ alkyl.

In some embodiments, R⁸ is selected from the group consisting of C₆₋₁₀aryl, 5- to 10-membered heteroaryl, —C₁₋₆alkylene(C₆₋₁₀ aryl) and—C₁₋₆alkylene(5- to 10-membered heteroaryl), wherein the C₆₋₁₀ aryl andthe C₆₋₁₀ aryl of —C₁₋₆alkylene(C₆₋₁₀ aryl) and the 5- to 10-memberedheteroaryl and the 5- to 10-membered heteroaryl of —C₁₋₆ alkylene(5- to10-membered heteroaryl) are optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen, —OH, —NO₂, and C₁₋₆ alkoxy, and wherein the C₁₋₆alkylene of—C₁₋₆ alkylene(C₆₋₁₀ aryl) and —C₁₋₆alkylene(5- to 10-memberedheteroaryl) is optionally substituted with one or more substituents eachindependently selected from the group consisting of halogen, —OH, —NO₂,C₁₋₆ alkoxy, and C₆₋₁₀ aryl.

In some embodiments, R⁸ is —C₁₋₃ alkylene(C₆₋₁₀ aryl), wherein the C₆₋₁₀aryl is optionally substituted with one or more substituents eachindependently selected from the group consisting of halogen, hydroxy,—NO₂, and C₁₋₆alkoxy, and wherein the C₁₋₃ alkylene is optionallysubstituted with one or more substituents each independently selectedfrom the group consisting of C₆₋₁₀ aryl.

In some embodiments, R⁸ is —C₁₋₃ alkylene(C₆₋₁₀ aryl), wherein the C₆₋₁₀aryl is optionally substituted with one or more substituents eachindependently selected from the group consisting of halogen, hydroxy,—NO₂, and C₁₋₆alkoxy.

In some embodiments, R⁸ is —C₁₋₂ alkylene(C₆₋₁₀ aryl), wherein the C₆₋₁₀aryl is optionally substituted with one or more substituents eachindependently selected from the group consisting of halogen, hydroxyl,—NO₂, and C₁₋₆ alkoxy. In some embodiments, R⁸ is —C₁₋₂ alkylene(C₆₋₁₀aryl), wherein the C₆₋₁₀ aryl is optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen, hydroxy and —NO₂. In some embodiments, R⁸ is —C₁₋₂alkylene(C₆₋₁₀ aryl), wherein the C₆₋₁₀ aryl is optionally substitutedwith one or more substituents each independently selected from the groupconsisting of halogen and hydroxy. In some embodiments, R⁸ is —C₁₋₂alkylene(C₆₋₁₀ aryl), wherein the C₆₋₁₀ aryl is optionally substitutedwith hydroxy. In other embodiments, R⁸ is —C₁₋₂ alkylene(C₆ aryl),wherein the C₆ aryl is optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen, hydroxyl, —NO₂, and C₁₋₆ alkoxy.

In some embodiments, R⁸ is —CH₂-phenyl or —CH₂-naphthyl, wherein phenylor naphthyl may be optionally substituted with 1 or 2 substituents eachindependently selected from the group consisting of halogen, hydroxy,—NO₂, and C₁₋₆ alkoxy. In other embodiments, R⁸ is —CH₂-phenyl or—CH₂-naphthyl, wherein the phenyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen, hydroxyl, and —NO₂. In some embodiments, R⁸ is —CH₂-phenylor —CH₂-naphthyl, wherein the phenyl is optionally substituted with oneor more substituents each independently selected from the groupconsisting of halogen and hydroxyl. In some embodiments, R⁸ is—CH₂-phenyl or —CH₂-naphthyl, wherein the phenyl is optionallysubstituted with hydroxyl.

In some embodiments, R⁸ is —CH₂-phenyl, wherein phenyl may be optionallysubstituted with 1 or 2 substituents each independently selected fromthe group consisting of halogen, hydroxy, —NO₂, and C₁₋₆alkoxy. In someembodiments, R⁸ is —CH₂-phenyl, wherein phenyl may be optionallysubstituted with 1 or 2 substituents each independently selected fromthe group consisting of halogen, hydroxy, and —NO₂. In some embodiments,R⁸ is —CH₂-phenyl, wherein phenyl is unsubstituted. In some embodiments,R⁸ is —CH₂-phenyl, wherein phenyl is substituted with 1 or 2substituents each independently selected from the group consisting ofhalogen, hydroxy, —NO₂, and C₁₋₆alkoxy. In some embodiments, R⁸ is—CH₂-phenyl, wherein phenyl is substituted with 1 or 2 substituents eachindependently selected from the group consisting of halogen, hydroxy,and —NO₂. In some embodiments, R⁸ is —CH₂-phenyl, wherein phenyl issubstituted with 1 or 2 substituents each independently selected fromthe group consisting of halogen and hydroxy.

In some embodiments, R⁸ is —CH₂-phenyl, wherein phenyl is substitutedwith 1 or 2 substituents each independently selected from the groupconsisting of —F, —Cl, —Br, and —I. In some embodiments, R⁸ is—CH₂-phenyl, wherein phenyl is substituted with 1 or 2 substituents eachof which is —F. In some embodiments, R⁸ is —CH₂-phenyl, wherein phenylis substituted with 1 or 2 substituents each of which is —Cl. In someembodiments, R⁸ is —CH₂-phenyl, wherein phenyl is substituted with 1 or2 substituents each of which is —Br. In some embodiments, R⁸ is—CH₂-phenyl, wherein phenyl is substituted with 1 or 2 substituents eachof which is —I. In some embodiments, R⁸ is —CH₂-phenyl, wherein phenylis substituted with 1 substituent which is —F. In some embodiments, R⁸is —CH₂-phenyl, wherein phenyl is substituted with 1 substituent whichis —Cl. In some embodiments, R⁸ is —CH₂-phenyl, wherein phenyl issubstituted with 1 substituent which is —Br. In some embodiments, R⁸ is—CH₂-phenyl, wherein phenyl is substituted with 1 substituent which is—I.

In some embodiments, R⁸ is —CH₂-phenyl, wherein phenyl is substitutedwith 1 or 2 substituents each of which is hydroxy. In some embodiments,R⁸ is —CH₂-phenyl, wherein phenyl is substituted with 1 substituentwhich is hydroxy. In some embodiments, R⁸ is —CH₂-phenyl, wherein phenylis substituted with 1 or 2 substituents each of which is —NO₂. In someembodiments, R⁸ is —CH₂-phenyl, wherein phenyl is substituted with 1substituent which is —NO₂. In some embodiments, R⁸ is —CH₂-phenyl,wherein phenyl is substituted with 1 or 2 substituents each of which isindependently C₁₋₆alkoxy. In some embodiments, R⁸ is —CH₂-phenyl,wherein phenyl is substituted with 1 or 2 substituents each of which isindependently C₁₋₃ alkoxy. In some embodiments, R⁸ is —CH₂-phenyl,wherein phenyl is substituted with 1 substituent which is methoxy.

In some embodiments, R⁸ is

wherein R¹⁵¹ is H, halogen, hydroxyl or C₁₋₃ alkoxy. In someembodiments, R¹⁵¹ is H, halogen or hydroxyl. In some embodiments, R¹⁵¹is H, Cl or hydroxyl. In some embodiments, R¹⁵¹ is Cl or hydroxyl. Insome embodiments, R¹⁵¹ is hydroxyl.

In some embodiments, R⁸ is —C₁₋₂ alkylene(C₁₀ aryl), wherein the C₁₀aryl is optionally substituted with one or more substituents eachindependently selected from the group consisting of halogen, hydroxyland —NO₂, and C₁₋₆ alkoxy. In some embodiments, R⁸ is —CH₂-naphthyl.

In some embodiments, R⁸ is selected from the group consisting of—CH₂-pyridinyl, —CH₂— indolyl, —CH₂-thiophenyl, —CH₂-thiazolyl,—CH₂-furanyl, —CH₂-benzothiophenyl, and —CH₂— imidazolyl. In someembodiments, R⁸ is —CH₂-pyridinyl. In some embodiments, R⁸ is—CH₂-indolyl. In some embodiments, R⁸ is —CH₂-thiophenyl. In someembodiments, R⁸ is —CH₂-thiazolyl. In some embodiments, R⁸ is—CH₂-furanyl. In some embodiments, R⁸ is —CH₂-benzothiophenyl. In someembodiments, R⁸ is —CH₂-imidazolyl.

Embodiments of R⁹, R¹, R¹¹, R¹², R¹³, R¹⁴ and R¹⁵

In some embodiments, R⁹ is H or C₁₋₆ alkyl. In other embodiments, R⁹ isH or C₁₋₅ alkyl. In some embodiments, R⁹ is H or C₁₋₄ alkyl. In someembodiments, R⁹ is H or C₁₋₃ alkyl. In other embodiments, R⁹ is H orC₁₋₂ alkyl. In some embodiments, R⁹ is H or CH₃. In some embodiments, R⁹is H. In other embodiments, R⁹ is CH₃. In some embodiments, R¹⁰ is H orC₁₋₆ alkyl. In other embodiments, R¹⁰ is H or C₁₋₅ alkyl. In someembodiments, R¹⁰ is H or C₁₋₄ alkyl. In some embodiments, R¹⁰ is H orC₁₋₃ alkyl. In other embodiments, R¹⁰ is H or C₁₋₂ alkyl. In someembodiments, R¹⁰ is H or CH₃. In some embodiments, R¹⁰ is H. In otherembodiments, R¹⁰ is CH₃. In some embodiments, R¹¹ is H or C₁₋₆ alkyl. Inother embodiments, R¹¹ is H or C₁₋₅ alkyl. In some embodiments, R¹¹ is Hor C₁₋₄ alkyl. In some embodiments, R¹¹ is H or C₁₋₃ alkyl. In otherembodiments, R¹¹ is H or C₁₋₂ alkyl. In some embodiments, R¹¹ is H orCH₃. In some embodiments, R¹¹ is H. In other embodiments, R¹¹ is CH₃. Insome embodiments, R¹² is H or C₁₋₆ alkyl. In other embodiments, R¹² is Hor C₁₋₅ alkyl. In some embodiments, R¹² is H or C₁₋₄ alkyl. In someembodiments, R¹² is H or C₁₋₃ alkyl. In other embodiments, R¹² is H orC₁₋₂ alkyl. In some embodiments, R¹² is H or CH₃. In some embodiments,R¹² is H. In other embodiments, R¹² is CH₃. In some embodiments, R¹³ isH or C₁₋₆ alkyl. In other embodiments, R¹³ is H or C₁₋₅ alkyl. In someembodiments, R¹³ is H or C₁₋₄ alkyl. In some embodiments, R¹³ is H orC₁₋₃ alkyl. In other embodiments, R¹³ is H or C₁₋₂ alkyl. In someembodiments, R¹³ is H or CH₃. In some embodiments, R¹³ is H. In otherembodiments, R¹³ is CH₃. In some embodiments, R¹⁴ is H or C₁₋₆ alkyl. Inother embodiments, R¹⁴ is H or C₁₋₅ alkyl. In some embodiments, R¹⁴ is Hor C₁₋₄ alkyl. In some embodiments, R¹⁴ is H or C₁₋₃ alkyl. In otherembodiments, R¹⁴ is H or C₁₋₂ alkyl. In some embodiments, R¹⁴ is H orCH₃. In some embodiments, R¹⁴ is H. In other embodiments, R¹⁴ is CH₃. Insome embodiments, R¹⁵ is H or C₁₋₆ alkyl. In other embodiments, R¹⁵ is Hor C₁₋₅ alkyl. In some embodiments, R¹⁵ is H or C₁₋₄ alkyl. In someembodiments, R¹⁵ is H or C₁₋₃ alkyl. In other embodiments, R¹⁵ is H orC₁₋₂ alkyl. In some embodiments, R¹⁵ is H or CH₃. In some embodiments,R¹⁵ is H. In other embodiments, R¹⁵ is CH₃. In other embodiments, eachof R⁹, R¹⁰, R¹, R¹², R¹³, R¹⁴ and R¹⁵ is independently H or CH₃. In someembodiments, each of R⁹, R¹⁰, R¹, R¹², R¹³, R¹⁴ and R¹⁵ is H.

Embodiments of L

In some embodiments, L is selected from the group consisting of:

wherein X is S or O; and vii)

For each L moiety, either point of attachment may bond to either of thetwo carbon atoms on the remainder of the compound of Formula I or II towhich L is bonded (as set out in Formula I or II above) provided thatthey are not bonded to the same carbon atom. In other words, the Lmoieties set out herein are able to bond to the remainder of thecompound of Formula I or II in either direction. In some embodiments, Lis

L may be made using techniques known to a person of skill in the art.For example, when L is

suitable methods are described in Lin Chen, L., et al., “Disulfide BondFormation in Peptides”, Current Protocols in Protein Science (2001)18.6.1-18.6.19, John Wiley & Sons, Inc. In some embodiments, L is

When L is

suitable methods are described in, Rew, Y., et al. “Synthesis andBiological Activities of Cyclic Lanthionine Enkephalin Analogues:6-Opioid Receptor Selective Ligands”, J. Med. Chem., 2002, 45 (17), pp3746-3754; Bregant S., et al., “Orthogonally Protected Lanthionines:Synthesis and Use for the Solid-Phase Synthesis of an Analogue of NisinRing C'”, J. Org. Chem., 2005, 70 (7), pp 2430-2438; and Dugave, C., etal., “Synthesis of natural and non natural orthogonally protectedlanthionines from N-tritylserine and allo-threonine derivatives”,Tetrahedron: Asymmetry, Volume 8, Number 9, 8 May 1997, pp.1453-1465(13). In some embodiments, L is

When L is

suitable methods are described in Besret, S., et al.,“Thiocarbamate-linked peptides by chemoselective peptide ligation”,Journal of Peptide Science Volume 14, Issue 12, pages 1244-1250,December 2008. In some embodiments, L is

In some embodiments, L is

When L is

suitable methods are described in Stymiest, J. L., et al., “Synthesis ofBiologically Active Dicarba Analogues of the Peptide Hormone OxytocinUsing Ring-Closing Metathesis”, Org. Lett., 2003, 5 (1), pp 47-49. Insome embodiments, L is

wherein X is S or O. In some embodiments, L is

wherein X is S. In some embodiments, L is

wherein X is O. In some embodiments, L is

When L is

suitable methods are described in Holland-Nell, K., et al., “MaintainingBiological Activity by Using Triazoles as Disulfide Bond Mimetics”,Angewandte Chemie Int Ed 2011, 50, 5204-5206.

Embodiments of Chiral Centres *1, *2, *3, *4, *5, *6, *7, and *8

In some embodiments, chiral centre *1 is in the S configuration or the Rconfiguration. In some embodiments, chiral centre *1 is in the Sconfiguration. In some embodiments, chiral centre *1 is in the Rconfiguration. In some embodiments, chiral centre *2 is in the Sconfiguration or the R configuration. In some embodiments, chiral centre*2 is in the S configuration. In some embodiments, chiral centre *2 isin the R configuration. In some embodiments, chiral centre *3 is in theS configuration or the R configuration. In some embodiments, chiralcentre *3 is in the S configuration. In some embodiments, chiral centre*3 is in the R configuration. In some embodiments, chiral centre *4 isin the S configuration or the R configuration. In some embodiments,chiral centre *4 is in the S configuration. In some embodiments, chiralcentre *4 is in the R configuration. In some embodiments, chiral centre*5 is in the S configuration or the R configuration. In someembodiments, chiral centre *5 is in the S configuration. In someembodiments, chiral centre *5 is in the R configuration. In someembodiments, chiral centre *6 is in the S configuration or the Rconfiguration. In some embodiments, chiral centre *6 is in the Sconfiguration. In some embodiments, chiral centre *6 is in the Rconfiguration. In some embodiments, chiral centre *7 is in the Sconfiguration or the R configuration. In some embodiments, chiral centre*7 is in the S configuration. In some embodiments, chiral centre *7 isin the R configuration. In some embodiments, chiral centre *8 is in theS configuration or the R configuration. In some embodiments, chiralcentre *8 is in the S configuration. In some embodiments, chiral centre*8 is in the R configuration. In some embodiments, chiral centre *1 isin the S configuration or the R configuration, chiral centre *2 is inthe S configuration or the R configuration, chiral centre *3 is in the Sconfiguration or the R configuration, chiral centre *4 is in the Sconfiguration or the R configuration, chiral centre *5 is in the Sconfiguration or the R configuration, chiral centre *6 is in the Sconfiguration or the R configuration, chiral centre *7 is in the Sconfiguration or the R configuration, and chiral centre *8 is in the Sconfiguration or the R configuration. In some embodiments, chiral centre*1 is in the S configuration or the R configuration, chiral centre *2 isin the S configuration, chiral centre *3 is in the S configuration orthe R configuration, chiral centre *4 is in the S configuration or the Rconfiguration, chiral centre *5 is in the S configuration, chiral centre*6 is in the S configuration or the R configuration, chiral centre *7 isin the R configuration, and chiral centre *8 is in the S configurationor the R configuration. In some embodiments, chiral centre *1 is in theS configuration or the R configuration, chiral centre *2 is in the Sconfiguration or the R configuration, chiral centre *3 is in the Sconfiguration or the R configuration, chiral centre *4 is in the Sconfiguration or the R configuration, chiral centre *5 is in the Sconfiguration, chiral centre *6 is in the S configuration or the Rconfiguration, chiral centre *7 is in the R configuration, and chiralcentre *8 is in the S configuration or the R configuration. In someembodiments, chiral centre *1 is in the S configuration, chiral centre*2 is in the S configuration or the R configuration, chiral centre *3 isin the S configuration, chiral centre *4 is in the R configuration,chiral centre *5 is in the S configuration, chiral centre *6 is in the Sconfiguration or the R configuration, chiral centre *7 is in the Rconfiguration, and chiral centre *8 is in the R configuration. In someembodiments, chiral centre *1 is in the S configuration, chiral centre*2 is in the S configuration, chiral centre *3 is in the Sconfiguration, chiral centre *4 is in the R configuration, chiral centre*5 is in the S configuration, chiral centre *6 is in the Sconfiguration, chiral centre *7 is in the R configuration, and chiralcentre *8 is in the R configuration. In some embodiments, chiral centre*1 is in the S configuration, chiral centre *2 is in the Rconfiguration, chiral centre *3 is in the S configuration, chiral centre*4 is in the R configuration, chiral centre *5 is in the Sconfiguration, chiral centre *6 is in the S configuration, chiral centre*7 is in the R configuration, and chiral centre *8 is in the Rconfiguration. In some embodiments, chiral centre *1 is in the Sconfiguration, chiral centre *2 is in the S configuration, chiral centre*3 is in the S configuration, chiral centre *4 is in the Rconfiguration, chiral centre *5 is in the S configuration, chiral centre*6 is in the R configuration, chiral centre *7 is in the Rconfiguration, and chiral centre *8 is in the R configuration. In someembodiments, chiral centre *1 is in the S configuration, chiral centre*2 is in the R configuration, chiral centre *3 is in the Sconfiguration, chiral centre *4 is in the R configuration, chiral centre*5 is in the S configuration, chiral centre *6 is in the Rconfiguration, chiral centre *7 is in the R configuration, and chiralcentre *8 is in the R configuration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula I or a salt thereof, wherein: R^(C) isOH or NHR¹⁶, wherein R¹⁶ is H or C₁₋₆ alkyl; R^(N) is selected from thegroup consisting of: (i) H; (ii) C₁₋₆ alkyl; (iii) —C(O)R¹⁷, wherein R⁷is selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and 5-to 10-membered heteroaryl; (iv) —C(O)C₁₋₃ alkylene-C(O)OR¹⁸, wherein R¹⁸is H or C₁₋₆ alkyl; (v) —C(O)C₁₋₃ alkylene-N(R²⁰)C(O)R¹⁹, wherein R¹⁹ isselected from the group consisting of C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to10-membered heteroaryl, and wherein R²⁰ is H or C₁₋₆alkyl; (vi)—C(O)C₁₋₃ alkylene-NR²¹R²², wherein each of R²¹ and R²² is independentlyselected from the group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5-to 10-membered heteroaryl; (vii) —C(O)C₁₋₃ alkylene-C(O)NR²³R²⁴, whereineach of R²³ and R²⁴ is independently selected from the group consistingof H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl; and(viii) —C(O)C₁₋₃ alkylene-S(O)₂R²⁵, wherein R²⁵ is selected from thegroup consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl; R¹ is —C₁₋₃ alkylene(C₆₋₁₀ aryl), wherein the C₆₋₁₀ aryl isoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, hydroxy, —NO₂, andC₁₋₆alkoxy; R³ is —C₁₋₃ alkylene(C₆₋₁₀ aryl), wherein the C₆₋₁₀ aryl isoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, hydroxy, —NO₂, and C₁₋₆alkoxy; R⁴ is selected from the group consisting of:

-   -   (i)

-   -   wherein each of R⁹⁰ and R⁹¹ is independently selected from the        group consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, wherein the C₁₋₆ alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆ alkoxy, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆ alkoxy, and wherein        n² is 3 or 4;    -   (ii)

-   -   wherein R⁹⁶ is selected from the group consisting of C₁₋₆alkyl,        C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the        C₁₋₆alkyl is optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein        the C₆₋₁₀ aryl and 5-to 10-membered heteroaryl are optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆ alkoxy, and wherein n³ is 3 or 4;    -   (iii)

-   -   wherein each of R⁹⁹ and R¹⁰⁰ is independently selected from the        group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein n⁴        is 1 or 2;    -   (iv)

-   -   wherein R¹⁰³ is selected from the group consisting of C₁₋₆alkyl,        C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered        heterocycloalkyl, wherein the C₁₋₆alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, hydroxy, —NO₂,        and C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl, 5- to 10-membered        heteroaryl, and 5- to 10-membered heterocycloalkyl are        optionally substituted with one or more substituents each        independently selected from the group consisting of halogen,        hydroxy, —NO₂, and C₁₋₆ alkoxy, and wherein n⁵ is 1 or 2;    -   (v)

-   -   wherein R¹¹⁰ is selected from the group consisting of H, C₁₋₆        alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, R¹¹¹ is        selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and        5- to 10-membered heteroaryl, wherein the C₁₋₆ alkyl of R¹¹⁰ or        R¹¹¹ is optionally substituted with one or more substituents        each independently selected from the group consisting of        halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl        and 5- to 10-membered heteroaryl of R¹⁰ or R¹¹ are optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆ alkoxy, and wherein n⁶ is 1 or 2;    -   (vi)

-   -   wherein R¹¹⁹ is selected from the group consisting of C₁₋₆alkyl,        C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the        C₁₋₆alkyl is optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, hydroxy, —NO₂, and C₁₋₆alkoxy, and        wherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are        optionally substituted with one or more substituents each        independently selected from the group consisting of halogen,        hydroxy, —NO₂, and C₁₋₆alkoxy, and wherein n⁸ is 1 or 2;    -   (vii)

-   -   wherein each of R¹²⁶ and R¹²⁷ is independently selected from the        group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein n⁹        is 1 or 2;    -   (viii)

-   -   wherein: each of R¹³⁴ and R¹³⁵ is independently selected from        the group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, 5- to        10-membered heteroaryl, —C(O)R¹³⁶, and —C(O)NR¹³⁷R¹³⁸, wherein        the C₁₋₆alkyl is optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆ alkoxy, and wherein        the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆alkoxy, and wherein n¹⁰ is 1 or 2, and wherein n¹¹ is 1 or        2;    -   R¹³⁶ is selected from the group consisting of C₁₋₆ alkyl, C₆₋₁₀        aryl, and 5- to 10-membered heteroaryl, wherein the C₁₋₆alkyl is        optionally substituted with one or more substituents each        independently selected from the group consisting of halogen,        —OH, —NO₂, and C₁₋₆ alkoxy, and wherein the C₆₋₁₀ aryl and 5- to        10-membered heteroaryl are optionally substituted with one or        more substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy; and each of        R¹³⁷ and R¹³⁸ is independently selected from the group        consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-membered        heteroaryl, wherein the C₁₋₆ alkyl is optionally substituted        with one or more substituents each independently selected from        the group consisting of halogen, —OH, —NO₂, and C₁₋₆ alkoxy, and        wherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are        optionally substituted with one or more substituents each        independently selected from the group consisting of halogen,        —OH, —NO₂, and C₁₋₆alkoxy;    -   (ix)

-   -   wherein each of R¹⁴⁴ and R¹⁴⁵ is independently selected from the        group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂,        C₁₋₆alkoxy, and 5- to 10-membered heterocycloalkyl, and wherein        the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂,        C₁₋₆alkoxy, and 5- to 10-membered heterocycloalkyl, and wherein        n¹² is 1 or 2;    -   (x)

-   -   wherein R¹⁴⁶ is selected from the group consisting of C₂₋₆        alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the        C₂₋₆ alkyl is optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, C₁₋₆ alkoxy, and 5- to        10-membered heterocycloalkyl, and wherein the C₆₋₁₀ aryl and 5-        to 10-membered heteroaryl are optionally substituted with one or        more substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, C₁₋₆alkoxy, and 5- to        10-membered heterocycloalkyl, and wherein n¹³ is 1 or 2;    -   (xi)

-   -   wherein R¹⁴⁸ is H or CH₃, R¹⁴⁹ is H or C₁₋₆ alkyl optionally        substituted with one or more substituents each independently        selected from the group consisting of hydroxyl, —COOH, —NH₂,        —C(O)NH₂, and —N(H)C(O)NH₂, and R¹⁵⁰ is H, CH₃ or acetyl, and        wherein n¹⁴ is 1 or 2; and    -   (xii)

-   -   wherein n¹⁵ is 1 or 2;        R⁵ is —NR⁷⁹R⁸⁰ and each of R⁷⁹ and R⁸⁰ is independently selected        from the group consisting of H, C₁₋₆ alkyl, —C(O)R⁸¹, and        —C(═NR⁸²)NR⁸³R³⁴, wherein R³¹ is C₁₋₆ alkyl and each of R⁸²,        R⁸³, and R³⁴ is H; n¹ is 3 or 4; R⁶ is C₁₋₆ alkyl optionally        substituted with hydroxyl; R⁸ is —C₁₋₃ alkylene(C₆₋₁₀ aryl),        wherein the C₆₋₁₀ aryl is optionally substituted with one or        more substituents each independently selected from the group        consisting of halogen, hydroxy, —NO₂, and C₁₋₆alkoxy; each of        R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, and R¹⁵ is independently H or CH₃;        L is

and chiral centre *1 is in the S configuration, chiral centre *2 is inthe S configuration, chiral centre *3 is in the S configuration, chiralcentre *4 is in the R configuration, chiral centre *5 is in the Sconfiguration, chiral centre *6 is in the S configuration, chiral centre*7 is in the R configuration, and chiral centre *8 is in the Rconfiguration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula I or a salt thereof, wherein: R^(C) isOH or NHR¹⁶, wherein R¹⁶ is H or C₁₋₆ alkyl; R^(N) is selected from thegroup consisting of: (i) H; (ii) C₁₋₆ alkyl; (iii) —C(O)R¹⁷, wherein R¹⁷is selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and 5-to 10-membered heteroaryl; (iv) —C(O)C₁₋₃ alkylene-C(O)OR¹⁸, wherein R¹⁸is H or C₁₋₆ alkyl; (v) —C(O)C₁₋₃ alkylene-N(R²⁰)C(O)R¹⁹, wherein R¹⁹ isselected from the group consisting of C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to10-membered heteroaryl, and wherein R²⁰ is H or C₁₋₆alkyl; (vi)—C(O)C₁₋₃ alkylene-NR²¹R²², wherein each of R²¹ and R²² is independentlyselected from the group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5-to 10-membered heteroaryl; (vii) —C(O)C₁₋₃ alkylene-C(O)NR²³R²⁴, whereineach of R²³ and R²⁴ is independently selected from the group consistingof H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl; and(viii) —C(O)C₁₋₃ alkylene-S(O)₂R²⁵, wherein R²⁵ is selected from thegroup consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl; R¹ is —C₁₋₃ alkylene(C₆₋₁₀ aryl), wherein the C₆₋₁₀ aryl isoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, hydroxy, —NO₂, andC₁₋₆alkoxy; R³ is —C₁₋₃ alkylene(C₆₋₁₀ aryl), wherein the C₆₋₁₀ aryl isoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, hydroxy, —NO₂, and C₁₋₆alkoxy;

R⁴ is selected from the group consisting of:

-   -   (i)

-   -   wherein each of R⁹⁰ and R⁹¹ is independently selected from the        group consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, wherein the C₁₋₆ alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆ alkoxy, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆ alkoxy, and wherein        n² is 3 or 4;    -   (iii)

-   -   wherein each of R⁹⁹ and R¹⁰⁰ is independently selected from the        group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein n⁴        is 1 or 2;    -   (iv)

-   -   wherein R¹⁰³ is selected from the group consisting of C₁₋₆alkyl,        C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered        heterocycloalkyl, wherein the C₁₋₆alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, hydroxy, —NO₂,        and C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl, 5- to 10-membered        heteroaryl, and 5- to 10-membered heterocycloalkyl are        optionally substituted with one or more substituents each        independently selected from the group consisting of halogen,        hydroxy, —NO₂, and C₁₋₆ alkoxy, and wherein n⁵ is 1 or 2;    -   (v)

-   -   wherein R¹¹⁰ is selected from the group consisting of H, C₁₋₆        alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, R¹¹¹ is        selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and        5- to 10-membered heteroaryl, wherein the C₁₋₆ alkyl of R¹¹⁰ or        R¹¹¹ is optionally substituted with one or more substituents        each independently selected from the group consisting of        halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl        and 5- to 10-membered heteroaryl of R¹⁰ or R¹¹ are optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆ alkoxy, and wherein n⁶ is 1 or 2;    -   (vi)

-   -   wherein R¹¹⁹ is selected from the group consisting of C₁₋₆alkyl,        C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the        C₁₋₆alkyl is optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, hydroxy, —NO₂, and C₁₋₆alkoxy, and        wherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are        optionally substituted with one or more substituents each        independently selected from the group consisting of halogen,        hydroxy, —NO₂, and C₁₋₆alkoxy, and wherein n⁸ is 1 or 2;    -   (viii)

-   -   wherein: each of R¹³⁴ and R¹³⁵ is independently selected from        the group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, 5- to        10-membered heteroaryl, —C(O)R¹³⁶, and —C(O)NR¹³⁷R¹³⁸, wherein        the C₁₋₆alkyl is optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆ alkoxy, and wherein        the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆alkoxy, and wherein n¹⁰ is 1 or 2, and wherein n¹¹ is 1 or        2;    -   R¹³⁶ is selected from the group consisting of C₁₋₆ alkyl, C₆₋₁₀        aryl, and 5- to 10-membered heteroaryl, wherein the C₁₋₆alkyl is        optionally substituted with one or more substituents each        independently selected from the group consisting of halogen,        —OH, —NO₂, and C₁₋₆ alkoxy, and wherein the C₆₋₁₀ aryl and 5- to        10-membered heteroaryl are optionally substituted with one or        more substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy; and each of        R¹³⁷ and R¹³⁸ is independently selected from the group        consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-membered        heteroaryl, wherein the C₁₋₆ alkyl is optionally substituted        with one or more substituents each independently selected from        the group consisting of halogen, —OH, —NO₂, and C₁₋₆ alkoxy, and        wherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are        optionally substituted with one or more substituents each        independently selected from the group consisting of halogen,        —OH, —NO₂, and C₁₋₆alkoxy;    -   (ix)

-   -   wherein each of R¹⁴⁴ and R¹⁴⁵ is independently selected from the        group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂,        C₁₋₆alkoxy, and 5- to 10-membered heterocycloalkyl, and wherein        the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂,        C₁₋₆alkoxy, and 5- to 10-membered heterocycloalkyl, and wherein        n¹² is 1 or 2; and    -   (xii)

-   -   wherein n¹⁵ is 1 or 2;        R⁵ is —NR⁷⁹R⁸⁰ and each of R⁷⁹ and R⁸⁰ is independently selected        from the group consisting of H, C₁₋₆ alkyl, —C(O)R⁸¹, and        —C(═NR⁸²)NR⁸³R⁸⁴, wherein R⁸¹ is C₁₋₆ alkyl and each of R⁸²,        R⁸³, and R⁸⁴ is H; n¹ is 3 or 4; R⁶ is C₁₋₆ alkyl optionally        substituted with hydroxyl; R⁸ is —C₁₋₃ alkylene(C₆₋₁₀ aryl),        wherein the C₆₋₁₀ aryl is optionally substituted with one or        more substituents each independently selected from the group        consisting of halogen, hydroxy, —NO₂, and C₁₋₆alkoxy; each of        R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, and R¹⁵ is independently H or CH₃;        L is

and chiral centre *1 is in the S configuration, chiral centre *2 is inthe S configuration, chiral centre *3 is in the S configuration, chiralcentre *4 is in the R configuration, chiral centre *5 is in the Sconfiguration, chiral centre *6 is in the S configuration, chiral centre*7 is in the R configuration, and chiral centre *8 is in the Rconfiguration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula I or a salt thereof, wherein: R^(C) isOH or NHR¹⁶, wherein R¹⁶ is H or C₁₋₆ alkyl; R^(N) is selected from thegroup consisting of: (i) H; (ii) C₁₋₆ alkyl; (iii) —C(O)R¹⁷, wherein R¹⁷is selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and 5-to 10-membered heteroaryl; (iv) —C(O)C₁₋₃ alkylene-C(O)OR¹⁸, wherein R¹⁸is H or C₁₋₆ alkyl; (v) —C(O)C₁₋₃ alkylene-N(R²⁰)C(O)R¹⁹, wherein R¹⁹ isselected from the group consisting of C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to10-membered heteroaryl, and wherein R²⁰ is H or C₁₋₆alkyl; (vi)—C(O)C₁₋₃ alkylene-NR²¹R²², wherein each of R²¹ and R²² is independentlyselected from the group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5-to 10-membered heteroaryl; (vii) —C(O)C₁₋₃ alkylene-C(O)NR²³R²⁴, whereineach of R²³ and R²⁴ is independently selected from the group consistingof H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl; and(viii) —C(O)C₁₋₃ alkylene-S(O)₂R²⁵, wherein R²⁵ is selected from thegroup consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl; R¹ is —C₁₋₃ alkylene(C₆₋₁₀ aryl), wherein the C₆₋₁₀ aryl isoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, hydroxy, —NO₂, andC₁₋₆alkoxy; R³ is —C₁₋₃ alkylene(C₆₋₁₀ aryl), wherein the C₆₋₁₀ aryl isoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, hydroxy, —NO₂, and C₁₋₆alkoxy; R⁴ is selected from the group consisting of:

-   -   (iii)

-   -   wherein each of R⁹⁹ and R¹⁰⁰ is independently selected from the        group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein n⁴        is 1 or 2; and    -   (v)

-   -   wherein R¹¹⁰ is selected from the group consisting of H, C₁₋₆        alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, R¹¹¹ is        selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and        5- to 10-membered heteroaryl, wherein the C₁₋₆ alkyl of R¹¹⁰ or        R¹¹¹ is optionally substituted with one or more substituents        each independently selected from the group consisting of        halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl        and 5- to 10-membered heteroaryl of R¹⁰ or R¹¹ are optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆ alkoxy, and wherein n⁶ is 1 or 2;        R⁵ is —NR⁷⁹R⁸⁰ and each of R⁷⁹ and R⁸⁰ is independently selected        from the group consisting of H, C₁₋₆ alkyl, —C(O)R⁸¹, and        —C(═NR⁸²)NR⁸³R⁸⁴, wherein R⁸¹ is C₁₋₆ alkyl and each of R⁸²,        R⁸³, and R⁸⁴ is H; n¹ is 3 or 4; R⁶ is C₁₋₆ alkyl optionally        substituted with hydroxyl; R⁸ is —C₁₋₃ alkylene(C₆₋₁₀ aryl),        wherein the C₆₋₁₀ aryl is optionally substituted with one or        more substituents each independently selected from the group        consisting of halogen, hydroxy, —NO₂, and C₁₋₆alkoxy; each of        R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, and R¹⁵ is independently H or CH₃;        L is

and chiral centre *1 is in the S configuration, chiral centre *2 is inthe S configuration, chiral centre *3 is in the S configuration, chiralcentre *4 is in the R configuration, chiral centre *5 is in the Sconfiguration, chiral centre *6 is in the S configuration, chiral centre*7 is in the R configuration, and chiral centre *8 is in the Rconfiguration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula I or a salt thereof, wherein: R^(C) isOH or NHR¹⁶, wherein R¹⁶ is H or C₁₋₆ alkyl; R^(N) is selected from thegroup consisting of: (i) H; (ii) C₁₋₆ alkyl; (iii) —C(O)R¹⁷, wherein R¹⁷is selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and 5-to 10-membered heteroaryl; (iv) —C(O)C₁₋₃ alkylene-C(O)OR¹⁸, wherein R¹⁸is H or C₁₋₆ alkyl; (v) —C(O)C₁₋₃ alkylene-N(R²⁰)C(O)R¹⁹, wherein R¹⁹ isselected from the group consisting of C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to10-membered heteroaryl, and wherein R²⁰ is H or C₁₋₆alkyl; (vi)—C(O)C₁₋₃ alkylene-NR²¹R²², wherein each of R²¹ and R²² is independentlyselected from the group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5-to 10-membered heteroaryl; (vii) —C(O)C₁₋₃ alkylene-C(O)NR²³R²⁴, whereineach of R²³ and R²⁴ is independently selected from the group consistingof H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl; and(viii) —C(O)C₁₋₃ alkylene-S(O)₂R²⁵, wherein R²⁵ is selected from thegroup consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl; R¹ is —C₁₋₃ alkylene(C₆₋₁₀ aryl), wherein the C₆₋₁₀ aryl isoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, hydroxy, —NO₂, andC₁₋₆alkoxy; R³ is —C₁₋₃ alkylene(C₆₋₁₀ aryl), wherein the C₆₋₁₀ aryl isoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, hydroxy, —NO₂, and C₁₋₆alkoxy; R⁴ is selected from the group consisting of: (iii)

wherein each of R⁹⁹ and R¹⁰⁰ is independently selected from the groupconsisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl, and wherein n⁴ is 1 or 2; and (v)

wherein R¹¹⁰ is selected from the group consisting of H, C₁₋₆alkyl,C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, and R¹¹¹ is selected fromthe group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl, and wherein n⁶ is 1 or 2; R⁵ is —NR⁷⁹R⁸⁰ and each of R⁷⁹ andR⁸⁰ is independently selected from the group consisting of H, C₁₋₆alkyl, —C(O)R⁸¹, and —C(═NR⁸²)NR⁸³R⁸⁴, wherein R⁸¹ is C₁₋₆ alkyl andeach of R⁸², R⁸³, and R⁸⁴ is H; n¹ is 3 or 4; R⁶ is C₁₋₆ alkyloptionally substituted with hydroxyl; R⁸ is —C₁₋₃ alkylene(C₆₋₁₀ aryl),wherein the C₆₋₁₀ aryl is optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen, hydroxy, —NO₂, and C₁₋₆ alkoxy; each of R⁹, R¹⁰, R¹¹, R¹², R¹³,R¹⁴, and R¹⁵ is independently H or CH₃; L is

and chiral centre *1 is in the S configuration, chiral centre *2 is inthe S configuration, chiral centre *3 is in the S configuration, chiralcentre *4 is in the R configuration, chiral centre *5 is in the Sconfiguration, chiral centre *6 is in the S configuration, chiral centre*7 is in the R configuration, and chiral centre *8 is in the Rconfiguration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula I or a salt thereof, wherein: R^(C) isOH or NHR¹⁶, wherein R¹⁶ is H or C₁₋₆ alkyl; R^(N) is selected from thegroup consisting of: (i) H; (ii) C₁₋₆ alkyl; (iii) —C(O)R¹⁷, wherein R¹⁷is selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and 5-to 10-membered heteroaryl; (iv) —C(O)C₁₋₃ alkylene-C(O)OR¹⁸, wherein R¹⁸is H or C₁₋₆ alkyl; (v) —C(O)C₁₋₃ alkylene-N(R²⁰)C(O)R¹⁹, wherein R¹⁹ isselected from the group consisting of C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to10-membered heteroaryl, and wherein R²⁰ is H or C₁₋₆alkyl; (vi)—C(O)C₁₋₃ alkylene-NR²¹R²², wherein each of R²¹ and R²² is independentlyselected from the group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5-to 10-membered heteroaryl; (vii) —C(O)C₁₋₃ alkylene-C(O)NR²³R²⁴, whereineach of R²³ and R²⁴ is independently selected from the group consistingof H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl; and(viii) —C(O)C₁₋₃ alkylene-S(O)₂R²⁵, wherein R²⁵ is selected from thegroup consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl; R¹ is —C₁₋₃ alkylene(C₆₋₁₀ aryl), wherein the C₆₋₁₀ aryl isoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, hydroxy, —NO₂, andC₁₋₆alkoxy; R³ is —C₁₋₃ alkylene(C₆₋₁₀ aryl), wherein the C₆₋₁₀ aryl isoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, hydroxy, —NO₂, and C₁₋₆alkoxy; R⁴ is selected from the group consisting of: (iii)

wherein each of R⁹⁹ and R¹⁰⁰ is independently selected from the groupconsisting of H and C₁₋₆ alkyl, and wherein n⁴ is 1 or 2; and (v)

wherein R¹¹⁰ is H, and R¹¹¹ is C₆ aryl, and wherein n⁶ is 1 or 2; R⁵ is—NR⁷⁹R⁸⁰ and each of R⁷⁹ and R⁸⁰ is independently selected from thegroup consisting of H, C₁₋₆ alkyl, —C(O)R⁸¹, and —C(═NR⁸²)NR⁸³R⁸⁴,wherein R⁸¹ is C₁₋₆ alkyl and each of R⁸², R⁸³, and R⁸⁴ is H; n¹ is 3 or4; R⁶ is C₁₋₆ alkyl optionally substituted with hydroxyl; R⁸ is —C₁₋₃alkylene(C₆₋₁₀ aryl), wherein the C₆₋₁₀ aryl is optionally substitutedwith one or more substituents each independently selected from the groupconsisting of halogen, hydroxy, —NO₂, and C₁₋₆alkoxy; each of R⁹, R¹⁰,R¹¹, R¹², R¹³, R¹⁴, and R¹⁵ is independently H or CH₃; L is

and chiral centre *1 is in the S configuration, chiral centre *2 is inthe S configuration, chiral centre *3 is in the S configuration, chiralcentre *4 is in the R configuration, chiral centre *5 is in the Sconfiguration, chiral centre *6 is in the S configuration, chiral centre*7 is in the R configuration, and chiral centre *8 is in the Rconfiguration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula I or a salt thereof, wherein: R^(C) isOH or NHR¹⁶, wherein R¹⁶ is H or C₁₋₆ alkyl; R^(N) is selected from thegroup consisting of: (i) H; (ii) C₁₋₆ alkyl; (iii) —C(O)R¹⁷, wherein R¹⁷is selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and 5-to 10-membered heteroaryl; (iv) —C(O)C₁₋₃ alkylene-C(O)OR¹⁸, wherein R¹⁸is H or C₁₋₆ alkyl; (v) —C(O)C₁₋₃ alkylene-N(R²⁰)C(O)R¹⁹, wherein R¹⁹ isselected from the group consisting of C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to10-membered heteroaryl, and wherein R²⁰ is H or C₁₋₆alkyl; (vi)—C(O)C₁₋₃ alkylene-NR²¹R²², wherein each of R²¹ and R²² is independentlyselected from the group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5-to 10-membered heteroaryl; (vii) —C(O)C₁₋₃ alkylene-C(O)NR²³R²⁴, whereineach of R²³ and R²⁴ is independently selected from the group consistingof H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl; and(viii) —C(O)C₁₋₃ alkylene-S(O)₂R²⁵, wherein R²⁵ is selected from thegroup consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl; R¹ is —C₁₋₃ alkylene(C₆₋₁₀ aryl), wherein the C₆₋₁₀ aryl isoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, hydroxy, —NO₂, andC₁₋₆alkoxy; R³ is —C₁₋₃ alkylene(C₆₋₁₀ aryl), wherein the C₆₋₁₀ aryl isoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, hydroxy, —NO₂, and C₁₋₆alkoxy; R⁴ is: (iii)

wherein each of R⁹⁹ and R¹⁰⁰ is independently selected from the groupconsisting of H and C₁₋₆ alkyl, and wherein n⁴ is 1 or 2; R⁵ is —NR⁷⁹R⁸⁰and each of R⁷⁹ and R⁸⁰ is independently selected from the groupconsisting of H, C₁₋₆ alkyl, —C(O)R⁸¹, and —C(═NR⁸²)NR⁸³R⁸⁴, wherein R⁸¹is C₁₋₆ alkyl and each of R⁸², R⁸³, and R⁸⁴ is H; n¹ is 3 or 4; R⁶ isC₁₋₆ alkyl optionally substituted with hydroxyl; R⁸ is —C₁₋₃alkylene(C₆₋₁₀ aryl), wherein the C₆₋₁₀ aryl is optionally substitutedwith one or more substituents each independently selected from the groupconsisting of halogen, hydroxy, —NO₂, and C₁₋₆alkoxy; each of R⁹, R¹⁰,R¹¹, R¹², R¹³, R¹⁴, and R¹⁵ is independently H or CH₃; L is

and chiral centre *1 is in the S configuration, chiral centre *2 is inthe S configuration, chiral centre *3 is in the S configuration, chiralcentre *4 is in the R configuration, chiral centre *5 is in the Sconfiguration, chiral centre *6 is in the S configuration, chiral centre*7 is in the R configuration, and chiral centre *8 is in the Rconfiguration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula I or a salt thereof, wherein: R^(C) isOH or NHR¹⁶, wherein R¹⁶ is H or C₁₋₆ alkyl; R^(N) is selected from thegroup consisting of: (i) H; (ii) C₁₋₆ alkyl; (iii) —C(O)R¹⁷, wherein R¹⁷is selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and 5-to 10-membered heteroaryl; (iv) —C(O)C₁₋₃ alkylene-C(O)OR¹⁸, wherein R¹⁸is H or C₁₋₆ alkyl; (v) —C(O)C₁₋₃ alkylene-N(R²⁰)C(O)R¹⁹, wherein R¹⁹ isselected from the group consisting of C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to10-membered heteroaryl, and wherein R²⁰ is H or C₁₋₆alkyl; (vi)—C(O)C₁₋₃ alkylene-NR²¹R²², wherein each of R²¹ and R²² is independentlyselected from the group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5-to 10-membered heteroaryl; (vii) —C(O)C₁₋₃ alkylene-C(O)NR²³R²⁴, whereineach of R²³ and R²⁴ is independently selected from the group consistingof H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl; and(viii) —C(O)C₁₋₃ alkylene-S(O)₂R²⁵, wherein R²⁵ is selected from thegroup consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl; R¹ is —C₁₋₃ alkylene(C₆₋₁₀ aryl), wherein the C₆₋₁₀ aryl isoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, hydroxy, —NO₂, andC₁₋₆alkoxy; R³ is —C₁₋₃ alkylene(C₆₋₁₀ aryl), wherein the C₆₋₁₀ aryl isoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, hydroxy, —NO₂, and C₁₋₆alkoxy; R⁴ is: (iii)

wherein each of R⁹⁹ and R¹⁰⁰ is H, and wherein n⁴ is 1 or 2; R⁵ is—NR⁷⁹R⁸⁰ and each of R⁷⁹ and R⁸⁰ is independently selected from thegroup consisting of H, C₁₋₆alkyl, —C(O)R⁸¹, and —C(═NR⁸²)NR⁸³R⁸⁴,wherein R⁸¹ is C₁₋₆ alkyl and each of R⁸², R⁸³, and R⁸⁴ is H; n¹ is 3 or4; R⁶ is C₁₋₆ alkyl optionally substituted with hydroxyl; R⁸ is —C₁₋₃alkylene(C₆₋₁₀ aryl), wherein the C₆₋₁₀ aryl is optionally substitutedwith one or more substituents each independently selected from the groupconsisting of halogen, hydroxy, —NO₂, and C₁₋₆ alkoxy; each of R⁹, R¹⁰,R¹¹, R¹², R¹³, R¹⁴, and R¹⁵ is independently H or CH₃; L is

and chiral centre *1 is in the S configuration, chiral centre *2 is inthe S configuration, chiral centre *3 is in the S configuration, chiralcentre *4 is in the R configuration, chiral centre *5 is in the Sconfiguration, chiral centre *6 is in the S configuration, chiral centre*7 is in the R configuration, and chiral centre *8 is in the Rconfiguration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula I or a salt thereof, wherein: R^(C) isOH or NHR¹⁶, wherein R¹⁶ is H or C₁₋₆ alkyl; R^(N) is selected from thegroup consisting of: (i) H; (ii) C₁₋₆ alkyl; (iii) —C(O)R¹⁷, wherein R⁷is selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and 5-to 10-membered heteroaryl; (iv) —C(O)C₁₋₃ alkylene-C(O)OR¹⁸, wherein R¹⁸is H or C₁₋₆ alkyl; (v) —C(O)C₁₋₃ alkylene-N(R²⁰)C(O)R¹⁹, wherein R¹⁹ isselected from the group consisting of C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to10-membered heteroaryl, and wherein R²⁰ is H or C₁₋₆alkyl; (vi)—C(O)C₁₋₃ alkylene-NR²¹R²², wherein each of R²¹ and R²² is independentlyselected from the group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5-to 10-membered heteroaryl; (vii) —C(O)C₁₋₃ alkylene-C(O)NR²³R²⁴, whereineach of R²³ and R²⁴ is independently selected from the group consistingof H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl; and(viii) —C(O)C₁₋₃ alkylene-S(O)₂R²⁵, wherein R²⁵ is selected from thegroup consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl; R¹ is —C₁₋₃ alkylene(C₆₋₁₀ aryl), wherein the C₆₋₁₀ aryl isoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, hydroxy, —NO₂, andC₁₋₆alkoxy; R³ is —C₁₋₃ alkylene(C₆₋₁₀ aryl), wherein the C₆₋₁₀ aryl isoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, hydroxy, —NO₂, and C₁₋₆alkoxy; R⁴ is or

R⁵ is —NR⁷⁹R⁸⁰ and each of R⁷⁹ and R⁸⁰ is independently selected fromthe group consisting of H, C₁₋₆alkyl, —C(O)R⁸¹, and —C(═NR⁸²)NR⁸³R⁸⁴,wherein R⁸¹ is C₁₋₆ alkyl and each of R⁸², R⁸³, and R⁸⁴ is H; n¹ is 3 or4; R⁶ is C₁₋₆ alkyl optionally substituted with hydroxyl; R⁸ is —C₁₋₃alkylene(C₆₋₁₀ aryl), wherein the C₆₋₁₀ aryl is optionally substitutedwith one or more substituents each independently selected from the groupconsisting of halogen, hydroxy, —NO₂, and C₁₋₆alkoxy; each of R⁹, R¹⁰,R¹¹, R¹², R¹³, R¹⁴, and R¹⁵ is independently H or CH₃; L is

and chiral centre *1 is in the S configuration, chiral centre *2 is inthe S configuration, chiral centre *3 is in the S configuration, chiralcentre *4 is in the R configuration, chiral centre *5 is in the Sconfiguration, chiral centre *6 is in the S configuration, chiral centre*7 is in the R configuration, and chiral centre *8 is in the Rconfiguration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula I or a salt thereof, wherein: R^(C) isOH or NHR¹⁶, wherein R¹⁶ is H or C₁₋₆ alkyl;

R^(N) is selected from the group consisting of: (i) H; (ii) C₁₋₆ alkyl;(iii) —C(O)R¹⁷, wherein R¹⁷ is selected from the group consisting ofC₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl; (iv) —C(O)C₁₋₃alkylene-C(O)OR¹⁸, wherein R¹⁸ is H or C₁₋₆ alkyl; (v) —C(O)C₁₋₃alkylene-N(R²⁰)C(O)R¹⁹, wherein R¹⁹ is selected from the groupconsisting of C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl,and wherein R²⁰ is H or C₁₋₆ alkyl; (vi) —C(O)C₁₋₃ alkylene-NR²¹R²²,wherein each of R²¹ and R²² is independently selected from the groupconsisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl; (vii) —C(O)C₁₋₃ alkylene-C(O)NR²³R²⁴, wherein each of R²³and R²⁴ is independently selected from the group consisting of H,C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl; and (viii)—C(O)C₁₋₃ alkylene-S(O)₂R²⁵, wherein R²⁵ is selected from the groupconsisting of C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl;R¹ is —C₁₋₃ alkylene(C₆₋₁₀ aryl), wherein the C₆₋₁₀ aryl is optionallysubstituted with one or more substituents each independently selectedfrom the group consisting of halogen, hydroxy, —NO₂, and C₁₋₆ alkoxy; R³is —C₁₋₃ alkylene(C₆₋₁₀ aryl), wherein the C₆₋₁₀ aryl is optionallysubstituted with one or more substituents each independently selectedfrom the group consisting of halogen, hydroxy, —NO₂, and C₁₋₆ alkoxy; R⁴is

R⁵ is —NR⁷⁹R⁸⁰ and each of R⁷⁹ and R⁸⁰ is independently selected fromthe group consisting of H, C₁₋₆alkyl, —C(O)R⁸¹, and —C(═NR⁸²)NR⁸³R⁸⁴,wherein R⁸¹ is C₁₋₆ alkyl and each of R⁸², R⁸³, and R⁸⁴ is H; n¹ is 3 or4; R⁶ is C₁₋₆ alkyl optionally substituted with hydroxyl; R⁸ is —C₁₋₃alkylene(C₆₋₁₀ aryl), wherein the C₆₋₁₀ aryl is optionally substitutedwith one or more substituents each independently selected from the groupconsisting of halogen, hydroxy, —NO₂, and C₁₋₆ alkoxy; each of R⁹, R¹⁰,R¹¹, R¹², R¹³, R¹⁴, and R¹⁵ is independently H or CH₃; L is

and chiral centre *1 is in the S configuration, chiral centre *2 is inthe S configuration, chiral centre *3 is in the S configuration, chiralcentre *4 is in the R configuration, chiral centre *5 is in the Sconfiguration, chiral centre *6 is in the S configuration, chiral centre*7 is in the R configuration, and chiral centre *8 is in the Rconfiguration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula I or a salt thereof, wherein: R^(C) isOH or NH₂; R^(N) is selected from the group consisting of H, C₁₋₃ alkyl,—C(O)R¹⁷, —C(O)C₁₋₃ alkylene-C(O)OR¹⁸, —C(O)C₁₋₃ alkylene-N(R²⁰)C(O)R¹⁹,—C(O)C₁₋₃ alkylene-NR²¹R²², —C(O)C₁₋₃ alkylene-C(O)NR²³R²⁴, and—C(O)C₁₋₃ alkylene-S(O)₂R²⁵, wherein R¹⁷ is C₁₋₆ alkyl or 5- to6-membered heteroaryl, R¹⁸ is C₁₋₃ alkyl, R¹⁹ is C₁₋₃ alkyl or C₆ aryl,each of R²⁰, R²¹, R²², R²³ and R²⁴ is H, and R²⁵ is C₆ aryl; R¹ is

wherein R⁸⁸ is H, halogen, hydroxyl or C₁₋₃ alkoxy; R³ is

wherein R⁸⁹ is H, halogen, hydroxyl or C₁₋₃ alkoxy; R⁴ is selected fromthe group consisting of:

-   -   (i)

-   -   wherein each of R⁹⁰ and R⁹¹ is independently selected from the        group consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, wherein the C₁₋₆ alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆ alkoxy, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆ alkoxy, and wherein        n² is 3 or 4;    -   (ii)

-   -   wherein R⁹⁶ is selected from the group consisting of C₁₋₆alkyl,        C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the        C₁₋₆alkyl is optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein        the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆ alkoxy, and wherein n³ is 3 or 4;    -   (iii)

-   -   wherein each of R⁹⁹ and R¹⁰⁰ is independently selected from the        group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein n⁴        is 1 or 2;    -   (iv)

-   -   wherein R¹⁰³ is selected from the group consisting of C₁₋₆alkyl,        C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered        heterocycloalkyl, wherein the C₁₋₆alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, hydroxy, —NO₂,        and C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl, 5- to 10-membered        heteroaryl, and 5- to 10-membered heterocycloalkyl are        optionally substituted with one or more substituents each        independently selected from the group consisting of halogen,        hydroxy, —NO₂, and C₁₋₆ alkoxy, and wherein n⁵ is 1 or 2;    -   (v)

-   -   wherein R¹⁰ is selected from the group consisting of H, C₁₋₆        alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, R¹¹¹ is        selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and        5- to 10-membered heteroaryl, wherein the C₁₋₆ alkyl of R¹¹⁰ or        R¹¹¹ is optionally substituted with one or more substituents        each independently selected from the group consisting of        halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl        and 5- to 10-membered heteroaryl of R¹⁰ or R¹¹ are optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆ alkoxy, and wherein n⁶ is 1 or 2;    -   (vi)

-   -   wherein R¹¹⁹ is selected from the group consisting of C₁₋₆        alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the        C₁₋₆alkyl is optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, hydroxy, —NO₂, and C₁₋₆alkoxy, and        wherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are        optionally substituted with one or more substituents each        independently selected from the group consisting of halogen,        hydroxy, —NO₂, and C₁₋₆alkoxy, and wherein n⁸ is 1 or 2;    -   (vii)

-   -   wherein each of R¹²⁶ and R¹²⁷ is independently selected from the        group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein n⁹        is 1 or 2;    -   (viii)

-   -   wherein: each of R¹³⁴ and R¹³⁵ is independently selected from        the group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, 5- to        10-membered heteroaryl, —C(O)R¹³⁶, and —C(O)NR¹³⁷R¹³⁸, wherein        the C₁₋₆alkyl is optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆ alkoxy, and wherein        the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆alkoxy, and wherein n¹⁰ is 1 or 2, and wherein n¹¹ is 1 or        2;    -   R¹³⁶ is selected from the group consisting of C₁₋₆ alkyl, C₆₋₁₀        aryl, and 5- to 10-membered heteroaryl, wherein the C₁₋₆alkyl is        optionally substituted with one or more substituents each        independently selected from the group consisting of halogen,        —OH, —NO₂, and C₁₋₆ alkoxy, and wherein the C₆₋₁₀ aryl and 5- to        10-membered heteroaryl are optionally substituted with one or        more substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy; and    -   each of R¹³⁷ and R¹³⁸ is independently selected from the group        consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-membered        heteroaryl, wherein the C₁₋₆ alkyl is optionally substituted        with one or more substituents each independently selected from        the group consisting of halogen, —OH, —NO₂, and C₁₋₆ alkoxy, and        wherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are        optionally substituted with one or more substituents each        independently selected from the group consisting of halogen,        —OH, —NO₂, and C₁₋₆alkoxy;    -   (ix)

-   -   wherein each of R¹⁴⁴ and R¹⁴⁵ is independently selected from the        group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂,        C₁₋₆alkoxy, and 5- to 10-membered heterocycloalkyl, and wherein        the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂,        C₁₋₆alkoxy, and 5- to 10-membered heterocycloalkyl, and wherein        n¹² is 1 or 2;    -   (x)

-   -   wherein R¹⁴⁶ is selected from the group consisting of C₂₋₆        alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the        C₂₋₆ alkyl is optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, C₁₋₆ alkoxy, and 5- to        10-membered heterocycloalkyl, and wherein the C₆₋₁₀ aryl and 5-        to 10-membered heteroaryl are optionally substituted with one or        more substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, C₁₋₆alkoxy, and 5- to        10-membered heterocycloalkyl, and wherein n¹³ is 1 or 2;    -   (xi)

-   -   wherein R¹⁴⁸ is H or CH₃, R¹⁴⁹ is H or C₁₋₆ alkyl optionally        substituted with one or more substituents each independently        selected from the group consisting of hydroxyl, —COOH, —NH₂,        —C(O)NH₂, and —N(H)C(O)NH₂, and R¹⁵⁰ is H, CH₃ or acetyl, and        wherein n¹⁴ is 1 or 2; and    -   (xii)

-   -   wherein n¹⁵ is 1 or 2;        R⁵ is —NH₂, —NHCH₃ or —N(CH₃)₂; n¹ is 4; R⁶ is selected from the        group consisting of —CH(CH₃)OH, —CH(CH₃)₂, —C(CH₃)₃, —CH₂OH and        —CH₂CH₃; R³ is

wherein R¹⁵¹ is H, halogen, hydroxyl or C₁₋₃ alkoxy; each of R⁹, R¹⁰,R¹¹, R¹², R¹³, R¹⁴, and R¹⁵ is H; L is

and chiral centre *1 is in the S configuration, chiral centre *2 is inthe S configuration, chiral centre *3 is in the S configuration, chiralcentre *4 is in the R configuration, chiral centre *5 is in the Sconfiguration, chiral centre *6 is in the S configuration, chiral centre*7 is in the R configuration, and chiral centre *8 is in the Rconfiguration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula I or a salt thereof, wherein: R^(C) isOH or NH₂; R^(N) is selected from the group consisting of H, C₁₋₃ alkyl,—C(O)R¹⁷, —C(O)C₁₋₃ alkylene-C(O)OR¹¹⁸, —C(O)C₁₋₃alkylene-N(R²⁰)C(O)R¹⁹, —C(O)C₁₋₃ alkylene-NR²¹R²², —C(O)C₁₋₃alkylene-C(O)NR²³R²⁴, and —C(O)C₁₋₃ alkylene-S(O)₂R²⁵, wherein R¹⁷ isC₁₋₆ alkyl or 5- to 6-membered heteroaryl, R¹⁸ is C₁₋₃ alkyl, R¹⁹ isC₁₋₃ alkyl or C₆ aryl, each of R²⁰, R²¹, R²², R²³ and R²⁴ is H, and R²⁵is C₆ aryl; R¹ is

wherein R⁸⁸ is H, halogen, hydroxyl or C₁₋₃ alkoxy; R³ is

wherein R⁸⁹ is H, halogen, hydroxyl or C₁₋₃ alkoxy;R⁴ is selected from the group consisting of:

-   -   (i)

-   -   wherein each of R⁹⁰ and R⁹¹ is independently selected from the        group consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, wherein the C₁₋₆ alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆ alkoxy, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆ alkoxy, and wherein        n² is 3 or 4;    -   (iii)

-   -   wherein each of R⁹⁹ and R¹⁰⁰ is independently selected from the        group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein n⁴        is 1 or 2;    -   (iv)

-   -   wherein R¹⁰³ is selected from the group consisting of C₁₋₆        alkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, and 5- to        10-membered heterocycloalkyl, wherein the C₁₋₆alkyl is        optionally substituted with one or more substituents each        independently selected from the group consisting of halogen,        hydroxy, —NO₂, and C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl, 5- to        10-membered heteroaryl, and 5- to 10-membered heterocycloalkyl        are optionally substituted with one or more substituents each        independently selected from the group consisting of halogen,        hydroxy, —NO₂, and C₁₋₆ alkoxy, and wherein n⁵ is 1 or 2;    -   (v)

-   -   wherein R¹¹⁰ is selected from the group consisting of H, C₁₋₆        alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, R¹¹¹ is        selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and        5- to 10-membered heteroaryl, wherein the C₁₋₆ alkyl of R¹¹⁰ or        R¹¹¹ is optionally substituted with one or more substituents        each independently selected from the group consisting of        halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl        and 5- to 10-membered heteroaryl of R¹⁰ or R¹¹ are optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆ alkoxy, and wherein n⁶ is 1 or 2;    -   (vi)

-   -   wherein R¹¹⁹ is selected from the group consisting of C₁₋₆alkyl,        C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the        C₁₋₆alkyl is optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, hydroxy, —NO₂, and C₁₋₆alkoxy, and        wherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are        optionally substituted with one or more substituents each        independently selected from the group consisting of halogen,        hydroxy, —NO₂, and C₁₋₆alkoxy, and wherein n⁸ is 1 or 2;    -   (viii)

-   -   wherein: each of R¹³⁴ and R¹³⁵ is independently selected from        the group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, 5- to        10-membered heteroaryl, —C(O)R¹³⁶, and —C(O)NR¹³⁷R¹³⁸, wherein        the C₁₋₆alkyl is optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆ alkoxy, and wherein        the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆alkoxy, and wherein n¹⁰ is 1 or 2, and wherein n¹¹ is 1 or        2;    -   R¹³⁶ is selected from the group consisting of C₁₋₆ alkyl, C₆₋₁₀        aryl, and 5- to 10-membered heteroaryl, wherein the C₁₋₆alkyl is        optionally substituted with one or more substituents each        independently selected from the group consisting of halogen,        —OH, —NO₂, and C₁₋₆ alkoxy, and wherein the C₆₋₁₀ aryl and 5- to        10-membered heteroaryl are optionally substituted with one or        more substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy; and    -   each of R¹³⁷ and R¹³⁸ is independently selected from the group        consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-membered        heteroaryl, wherein the C₁₋₆ alkyl is optionally substituted        with one or more substituents each independently selected from        the group consisting of halogen, —OH, —NO₂, and C₁₋₆ alkoxy, and        wherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are        optionally substituted with one or more substituents each        independently selected from the group consisting of halogen,        —OH, —NO₂, and C₁₋₆alkoxy;    -   (ix)

-   -   wherein each of R¹⁴⁴ and R¹⁴⁵ is independently selected from the        group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂,        C₁₋₆alkoxy, and 5- to 10-membered heterocycloalkyl, and wherein        the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂,        C₁₋₆alkoxy, and 5- to 10-membered heterocycloalkyl, and wherein        n¹² is 1 or 2; and    -   (xii)

-   -   wherein n¹⁵ is 1 or 2;        R⁵ is —NH₂, —NHCH₃ or —N(CH₃)₂; n¹ is 4; R⁶ is selected from the        group consisting of —CH(CH₃)OH, —CH(CH₃)₂, —C(CH₃)₃, —CH₂OH and        —CH₂CH₃; R⁸ is

wherein R¹⁵¹ is H, halogen, hydroxyl or C₁₋₃ alkoxy; each of R⁹, R¹⁰,R¹¹, R¹², R¹³, R¹⁴, and R¹⁵ is H; L is

and chiral centre *1 is in the S configuration, chiral centre *2 is inthe S configuration, chiral centre *3 is in the S configuration, chiralcentre *4 is in the R configuration, chiral centre *5 is in the Sconfiguration, chiral centre *6 is in the S configuration, chiral centre*7 is in the R configuration, and chiral centre *8 is in the Rconfiguration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula I or a salt thereof, wherein: R^(C) isOH or NH₂; R^(N) is selected from the group consisting of H, C₁₋₃ alkyl,—C(O)R¹⁷, —C(O)C₁₋₃ alkylene-C(O)OR¹⁸, —C(O)C₁₋₃ alkylene-N(R²⁰)C(O)R¹⁹,—C(O)C₁₋₃ alkylene-NR²¹R²², —C(O)C₁₋₃ alkylene-C(O)NR²³R²⁴, and—C(O)C₁₋₃ alkylene-S(O)₂R²⁵, wherein R¹⁷ is C₁₋₆ alkyl or 5- to6-membered heteroaryl, R¹⁸ is C₁₋₃ alkyl, R¹⁹ is C₁₋₃ alkyl or C₆ aryl,each of R²⁰, R²¹, R²², R²³ and R²⁴ is H, and R²⁵ is C₆ aryl; R¹ is

wherein R⁸⁸ is H, halogen, hydroxyl or C₁₋₃ alkoxy; R³ is

wherein R⁸⁹ is H, halogen, hydroxyl or C₁₋₃ alkoxy;R⁴ is selected from the group consisting of:

-   -   (iii)

-   -   wherein each of R⁹⁹ and R¹⁰⁰ is independently selected from the        group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein n⁴        is 1 or 2; and    -   (v)

-   -   wherein R¹¹⁰ is selected from the group consisting of H, C₁₋₆        alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, R¹¹¹ is        selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and        5- to 10-membered heteroaryl, wherein the C₁₋₆ alkyl of R¹¹⁰ or        R¹¹¹ is optionally substituted with one or more substituents        each independently selected from the group consisting of        halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl        and 5- to 10-membered heteroaryl of R¹⁰ or R¹¹ are optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆ alkoxy, and wherein n⁶ is 1 or 2;        R⁵ is —NH₂, —NHCH₃ or —N(CH₃)₂; n¹ is 4; R⁶ is selected from the        group consisting of —CH(CH₃)OH, —CH(CH₃)₂, —C(CH₃)₃, —CH₂OH and        —CH₂CH₃; R⁸ is

wherein R¹⁵¹ is H, halogen, hydroxyl or C₁₋₃ alkoxy; each of R⁹, R¹⁰,R¹¹, R¹², R¹³, R¹⁴, and R¹⁵ is H; L is

and chiral centre *1 is in the S configuration, chiral centre *2 is inthe S configuration, chiral centre *3 is in the S configuration, chiralcentre *4 is in the R configuration, chiral centre *5 is in the Sconfiguration, chiral centre *6 is in the S configuration, chiral centre*7 is in the R configuration, and chiral centre *8 is in the Rconfiguration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula I or a salt thereof, wherein: R^(C) isOH or NH₂; R^(N) is selected from the group consisting of H, C₁₋₃ alkyl,—C(O)R¹⁷, —C(O)C₁₋₃ alkylene-C(O)OR¹⁸, —C(O)C₁₋₃ alkylene-N(R²⁰)C(O)R¹⁹,—C(O)C₁₋₃ alkylene-NR²¹R²², —C(O)C₁₋₃ alkylene-C(O)NR²³R²⁴, and—C(O)C₁₋₃ alkylene-S(O)₂R²⁵, wherein R¹⁷ is C₁₋₆ alkyl or 5- to6-membered heteroaryl, R¹⁸ is C₁₋₃ alkyl, R¹⁹ is C₁₋₃ alkyl or C₆ aryl,each of R²⁰, R²¹, R²², R²³ and R²⁴ is H, and R²⁵ is C₆ aryl; R¹ is

wherein R⁸⁸ is H, halogen, hydroxyl or C₁₋₃ alkoxy; R³ is

wherein R⁸⁹ is H, halogen, hydroxyl or C₁₋₃ alkoxy;R⁴ is selected from the group consisting of:

-   -   (iii)

-   -   wherein each of R⁹⁹ and R¹⁰⁰ is independently selected from the        group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, and wherein n⁴ is 1 or 2; and    -   (v)

-   -   wherein R¹¹⁰ is selected from the group consisting of H, C₁₋₆        alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, and R¹¹¹ is        selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and        5- to 10-membered heteroaryl, and wherein n⁶ is 1 or 2;        R⁵ is —NH₂, —NHCH₃ or —N(CH₃)₂; n¹ is 4; R⁶ is selected from the        group consisting of —CH(CH₃)OH, —CH(CH₃)₂, —C(CH₃)₃, —CH₂OH and        —CH₂CH₃; R⁸ is

wherein R¹⁵¹ is H, halogen, hydroxyl or C₁₋₃alkoxy; each of R⁹, R¹⁰,R¹¹, R¹², R¹³, R¹⁴, and R¹⁵ is H; L

and chiral centre *1 is in the S configuration, chiral centre *2 is inthe S configuration, chiral centre *3 is in the S configuration, chiralcentre *4 is in the R configuration, chiral centre *5 is in the Sconfiguration, chiral centre *6 is in the S configuration, chiral centre*7 is in the R configuration, and chiral centre *8 is in the Rconfiguration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula I or a salt thereof, wherein: R^(C) isOH or NH₂; R^(N) is selected from the group consisting of H, C₁₋₃ alkyl,—C(O)R¹⁷, —C(O)C₁₋₃ alkylene-C(O)OR¹⁸, —C(O)C₁₋₃ alkylene-N(R²⁰)C(O)R¹⁹,—C(O)C₁₋₃ alkylene-NR²¹R²², —C(O)C₁₋₃ alkylene-C(O)NR²³R²⁴, and—C(O)C₁₋₃ alkylene-S(O)₂R²⁵, wherein R¹⁷ is C₁₋₆ alkyl or 5- to6-membered heteroaryl, R¹⁸ is C₁₋₃ alkyl, R¹⁹ is C₁₋₃ alkyl or C₆ aryl,each of R²⁰, R²¹, R²², R²³ and R²⁴ is H, and R²⁵ is C₆ aryl; R¹ is

wherein R⁸⁸ is H, halogen, hydroxyl or C₁₋₃ alkoxy; R³ is

wherein R⁸⁹ is H, halogen, hydroxyl or C₁₋₃ alkoxy; R⁴ is selected fromthe group consisting of: (iii)

wherein each of R⁹⁹ and R¹⁰⁰ is independently selected from the groupconsisting of H and C₁₋₆ alkyl, and wherein n⁴ is 1 or 2; and (v)

wherein R¹¹⁰ is H, and R¹¹¹ is C₆ aryl, and wherein n⁶ is 1 or 2; R⁵ is—NH₂, —NHCH₃ or —N(CH₃)₂; n¹ is 4; R⁶ is selected from the groupconsisting of —CH(CH₃)OH, —CH(CH₃)₂, —C(CH₃)₃, —CH₂OH and —CH₂CH₃; R⁸ is

wherein R¹⁵¹ is H, halogen, hydroxyl or C₁₋₃ alkoxy; each of R⁹, R¹⁰,R¹, R¹², R¹³, R¹⁴, and R¹⁵ is H; L is

and chiral centre *1 is in the S configuration, chiral centre *2 is inthe S configuration, chiral centre *3 is in the S configuration, chiralcentre *4 is in the R configuration, chiral centre *5 is in the Sconfiguration, chiral centre *6 is in the S configuration, chiral centre*7 is in the R configuration, and chiral centre *8 is in the Rconfiguration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula I or a salt thereof, wherein: R^(C) isOH or NH₂; R^(N) is selected from the group consisting of H, C₁₋₃ alkyl,—C(O)R¹⁷, —C(O)C₁₋₃ alkylene-C(O)OR¹¹⁸, —C(O)C₁₋₃alkylene-N(R²⁰)C(O)R¹⁹, —C(O)C₁₋₃ alkylene-NR²¹R²², —C(O)C₁₋₃alkylene-C(O)NR²³R²⁴, and —C(O)C₁₋₃ alkylene-S(O)₂R²⁵, wherein R¹⁷ isC₁₋₆ alkyl or 5- to 6-membered heteroaryl, R¹⁸ is C₁₋₃ alkyl, R¹⁹ isC₁₋₃ alkyl or C₆ aryl, each of R²⁰, R²¹, R²², R²³ and R²⁴ is H, and R²⁵is C₆ aryl; R¹ is

wherein R⁸⁸ is H, halogen, hydroxyl or C₁₋₃ alkoxy; R³ is

wherein R⁸⁹ is H, halogen, hydroxyl or C₁₋₃ alkoxy; R⁴ is: (iii)

wherein each of R⁹⁹ and R¹⁰⁰ is independently selected from the groupconsisting of H and C₁₋₆ alkyl, and wherein n⁴ is 1 or 2; R⁵ is —NH₂,—NHCH₃ or —N(CH₃)₂; n¹ is 4; R⁶ is selected from the group consisting of—CH(CH₃)OH, —CH(CH₃)₂, —C(CH₃)₃, —CH₂OH and —CH₂CH₃; R⁸ is

wherein R¹⁵¹ is H, halogen, hydroxyl or C₁₋₃ alkoxy; each of R⁹, R¹⁰,R¹¹, R¹², R¹³, R¹⁴, and R¹⁵ is H; L is

and chiral centre *1 is in the S configuration, chiral centre *2 is inthe S configuration, chiral centre *3 is in the S configuration, chiralcentre *4 is in the R configuration, chiral centre *5 is in the Sconfiguration, chiral centre *6 is in the S configuration, chiral centre*7 is in the R configuration, and chiral centre *8 is in the Rconfiguration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula I or a salt thereof, wherein: R^(C) isOH or NH₂; R^(N) is selected from the group consisting of H, C₁₋₃ alkyl,—C(O)R¹⁷, —C(O)C₁₋₃ alkylene-C(O)OR¹⁸, —C(O)C₁₋₃ alkylene-N(R²⁰)C(O)R¹⁹,—C(O)C₁₋₃ alkylene-NR²¹R²², —C(O)C₁₋₃ alkylene-C(O)NR²³R²⁴, and—C(O)C₁₋₃ alkylene-S(O)₂R²⁵, wherein R¹⁷ is C₁₋₆ alkyl or 5- to6-membered heteroaryl, R¹⁸ is C₁₋₃ alkyl, R¹⁹ is C₁₋₃ alkyl or C₆ aryl,each of R²⁰, R²¹, R²², R²³ and R²⁴ is H, and R²⁵ is C₆ aryl; R¹ is

wherein R⁸⁸ is H, halogen, hydroxyl or C₁₋₃ alkoxy; R³ is

wherein R⁸⁹ is H, halogen, hydroxyl or C₁₋₃ alkoxy; R⁴ is: (iii)

wherein each of R⁹⁹ and R¹⁰⁰ is H, and wherein n⁴ is 1 or 2; R⁵ is —NH₂,—NHCH₃ or —N(CH₃)₂; n¹ is 4; R⁶ is selected from the group consisting of—CH(CH₃)OH, —CH(CH₃)₂, —C(CH₃)₃, —CH₂OH and —CH₂CH₃; R⁸ is

wherein R¹⁵¹ is H, halogen, hydroxyl or C₁₋₃ alkoxy; each of R⁹, R¹⁰,R¹¹, R¹², R¹³, R¹⁴, and R¹⁵ is H; L is

and chiral centre *1 is in the S configuration, chiral centre *2 is inthe S configuration, chiral centre *3 is in the S configuration, chiralcentre *4 is in the R configuration, chiral centre *5 is in the Sconfiguration, chiral centre *6 is in the S configuration, chiral centre*7 is in the R configuration, and chiral centre *8 is in the Rconfiguration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula I or a salt thereof, wherein: R^(C) isOH or NH₂; R^(N) is selected from the group consisting of H, C₁₋₃ alkyl,—C(O)R¹⁷, —C(O)C₁₋₃ alkylene-C(O)OR¹⁸, —C(O)C₁₋₃ alkylene-N(R²⁰)C(O)R¹⁹,—C(O)C₁₋₃ alkylene-NR²¹R²², —C(O)C₁₋₃ alkylene-C(O)NR²³R²⁴, and—C(O)C₁₋₃ alkylene-S(O)₂R²⁵, wherein R¹⁷ is C₁₋₆ alkyl or 5- to6-membered heteroaryl, R¹⁸ is C₁₋₃ alkyl, R¹⁹ is C₁₋₃ alkyl or C₆ aryl,each of R²⁰, R²¹, R²², R²³ and R²⁴ is H, and R²⁵ is C₆ aryl; R¹ is

wherein R⁸⁸ is H, halogen, hydroxyl or C₁₋₃ alkoxy; R³ is

wherein R⁸⁹ is H, halogen, hydroxyl or C₁₋₃ alkoxy; R⁴ is

R⁵ is —NH₂, —NHCH₃ or —N(CH₃)₂; n¹ is 4; R⁶ is selected from the groupconsisting of —CH(CH₃)OH, —CH(CH₃)₂, —C(CH₃)₃, —CH₂OH and —CH₂CH₃; R⁸ is

wherein R¹⁵¹ is H, halogen, hydroxyl or C₁₋₃ alkoxy; each of R⁹, R¹⁰,R¹¹, R¹², R¹³, R¹⁴, and R¹⁵ is H; L is

and chiral centre *1 is in the S configuration, chiral centre *2 is inthe S configuration, chiral centre *3 is in the S configuration, chiralcentre *4 is in the R configuration, chiral centre *5 is in the Sconfiguration, chiral centre *6 is in the S configuration, chiral centre*7 is in the R configuration, and chiral centre *8 is in the Rconfiguration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula I or a salt thereof, wherein: R^(C) isOH or NH₂; R^(N) is selected from the group consisting of H, C₁₋₃ alkyl,—C(O)R¹⁷, —C(O)C₁₋₃ alkylene-C(O)OR¹¹⁸, —C(O)C₁₋₃alkylene-N(R²⁰)C(O)R¹⁹, —C(O)C₁₋₃ alkylene-NR²¹R²², —C(O)C₁₋₃alkylene-C(O)NR²³R²⁴, and —C(O)C₁₋₃ alkylene-S(O)₂R²⁵, wherein R¹⁷ isC₁₋₆ alkyl or 5- to 6-membered heteroaryl, R¹⁸ is C₁₋₃ alkyl, R¹⁹ isC₁₋₃ alkyl or C₆ aryl, each of R²⁰, R²¹, R²², R²³ and R²⁴ is H, and R²⁵is C₆ aryl; R¹ is

wherein R⁸⁸ is H, halogen, hydroxyl or C₁₋₃ alkoxy; R³ is

wherein R⁸⁹ is H, halogen, hydroxyl or C₁₋₃ alkoxy; R⁴ is

R⁵ is —NH₂, —NHCH₃ or —N(CH₃)₂; n¹ is 4; R⁶ is selected from the groupconsisting of —CH(CH₃)OH, —CH(CH₃)₂, —C(CH₃)₃, —CH₂OH and —CH₂CH₃; R⁸ is

wherein R¹⁵¹ is H, halogen, hydroxyl or C₁₋₃alkoxy; each of R⁹, R¹⁰,R¹¹, R¹², R¹³, R¹⁴, and R¹⁵ is H; L is

and chiral centre *1 is in the S configuration, chiral centre *2 is inthe S configuration, chiral centre *3 is in the S configuration, chiralcentre *4 is in the R configuration, chiral centre *5 is in the Sconfiguration, chiral centre *6 is in the S configuration, chiral centre*7 is in the R configuration, and chiral centre *8 is in the Rconfiguration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula I or a salt thereof, wherein: R^(C) isNH₂; R^(N) is selected from the group consisting of H, C₁₋₃ alkyl,—C(O)R¹⁷, —C(O)C₁₋₃ alkylene-C(O)OR¹⁸, —C(O)C₁₋₃ alkylene-N(R²⁰)C(O)R¹⁹,—C(O)C₁₋₃ alkylene-NR²¹R²², —C(O)C₁₋₃ alkylene-C(O)NR²³R²⁴, and—C(O)C₁₋₃ alkylene-S(O)₂R²⁵, wherein R¹⁷ is C₁₋₆ alkyl or 5- to6-membered heteroaryl, R¹⁸ is C₁₋₃ alkyl, R¹⁹ is C₁₋₃ alkyl or C₆ aryl,each of R²⁰, R²¹, R²², R²³ and R²⁴ is H, and R²⁵ is C₆ aryl; R¹ is

R³ is, wherein R⁸⁹ is Cl or hydroxyl; R⁴ is selected from the groupconsisting of:

-   -   (i)

-   -   wherein each of R⁹⁰ and R⁹¹ is independently selected from the        group consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, wherein the C₁₋₆ alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆ alkoxy, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆ alkoxy, and wherein        n² is 3 or 4;    -   (ii)

-   -   wherein R⁹⁶ is selected from the group consisting of C₁₋₆alkyl,        C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the        C₁₋₆alkyl is optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein        the C₆₋₁₀ aryl and 5-to 10-membered heteroaryl are optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆ alkoxy, and wherein n³ is 3 or 4;    -   (iii)

-   -   wherein each of R⁹⁹ and R¹⁰⁰ is independently selected from the        group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆alkoxyl, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein n⁴        is 1 or 2;    -   (iv)

-   -   wherein R¹⁰³ is selected from the group consisting of C₁₋₆alkyl,        C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered        heterocycloalkyl, wherein the C₁₋₆alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, hydroxy, —NO₂,        and C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl, 5- to 10-membered        heteroaryl, and 5- to 10-membered heterocycloalkyl are        optionally substituted with one or more substituents each        independently selected from the group consisting of halogen,        hydroxy, —NO₂, and C₁₋₆ alkoxy, and wherein n⁵ is 1 or 2;    -   (v)

-   -   wherein R¹¹⁰ is selected from the group consisting of H, C₁₋₆        alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, R¹¹¹ is        selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and        5- to 10-membered heteroaryl, wherein the C₁₋₆ alkyl of R¹¹⁰ or        R¹¹¹ is optionally substituted with one or more substituents        each independently selected from the group consisting of        halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl        and 5- to 10-membered heteroaryl of R¹⁰ or R¹¹ are optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆ alkoxy, and wherein n⁶ is 1 or 2;    -   (vi)

-   -   wherein R¹¹⁹ is selected from the group consisting of C₁₋₆alkyl,        C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the        C₁₋₆alkyl is optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, hydroxy, —NO₂, and C₁₋₆alkoxy, and        wherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are        optionally substituted with one or more substituents each        independently selected from the group consisting of halogen,        hydroxy, —NO₂, and C₁₋₆alkoxy, and wherein n⁸ is 1 or 2;    -   (vii)

-   -   wherein each of R¹²⁶ and R¹²⁷ is independently selected from the        group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein n⁹        is 1 or 2;    -   (viii)

-   -   wherein: each of R¹³⁴ and R¹³⁵ is independently selected from        the group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, 5- to        10-membered heteroaryl, —C(O)R¹¹⁶, and —C(O)NR¹³⁷R¹³⁸, wherein        the C₁₋₆alkyl is optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆ alkoxy, and wherein        the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆alkoxy, and wherein n¹⁰ is 1 or 2, and wherein n¹¹ is 1 or        2;    -   R¹³⁶ is selected from the group consisting of C₁₋₆ alkyl, C₆₋₁₀        aryl, and 5- to 10-membered heteroaryl, wherein the C₁₋₆alkyl is        optionally substituted with one or more substituents each        independently selected from the group consisting of halogen,        —OH, —NO₂, and C₁₋₆ alkoxy, and wherein the C₆₋₁₀ aryl and 5- to        10-membered heteroaryl are optionally substituted with one or        more substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy; and each of        R¹³⁷ and R¹³⁸ is independently selected from the group        consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-membered        heteroaryl, wherein the C₁₋₆ alkyl is optionally substituted        with one or more substituents each independently selected from        the group consisting of halogen, —OH, —NO₂, and C₁₋₆ alkoxy, and        wherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are        optionally substituted with one or more substituents each        independently selected from the group consisting of halogen,        —OH, —NO₂, and C₁₋₆alkoxy;    -   (ix)

-   -   wherein each of R¹⁴⁴ and R¹⁴⁵ is independently selected from the        group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂,        C₁₋₆alkoxy, and 5- to 10-membered heterocycloalkyl, and wherein        the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂,        C₁₋₆alkoxy, and 5- to 10-membered heterocycloalkyl, and wherein        n¹² is 1 or 2;    -   (x)

-   -   wherein R¹⁴⁶ is selected from the group consisting of C₂₋₆        alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the        C₂₋₆ alkyl is optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, C₁₋₆ alkoxy, and 5- to        10-membered heterocycloalkyl, and wherein the C₆₋₁₀ aryl and 5-        to 10-membered heteroaryl are optionally substituted with one or        more substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, C₁₋₆alkoxy, and 5- to        10-membered heterocycloalkyl, and wherein n¹³ is 1 or 2;    -   (xi)

-   -   wherein R¹⁴⁸ is H or CH₃, R¹⁴⁹ is H or C₁₋₆ alkyl optionally        substituted with one or more substituents each independently        selected from the group consisting of hydroxyl, —COOH, —NH₂,        —C(O)NH₂, and —N(H)C(O)NH₂, and R¹⁵⁰ is H, CH₃ or acetyl, and        wherein n¹⁴ is 1 or 2; and    -   (xii)

-   -   wherein n¹⁵ is 1 or 2;        R⁵ is —NH₂, —NHCH₃ or —N(CH₃)₂; n¹ is 4; R⁶ is —CH(CH₃)OH; R⁸ is

wherein R¹⁵¹ is Cl or hydroxyl; each of R⁹, R¹⁰, R¹¹, R¹², R³, R¹⁴, andR¹⁵ is H; L is

and chiral centre *1 is in the S configuration, chiral centre *2 is inthe S configuration, chiral centre *3 is in the S configuration, chiralcentre *4 is in the R configuration, chiral centre *5 is in the Sconfiguration, chiral centre *6 is in the S configuration, chiral centre*7 is in the R configuration, and chiral centre *8 is in the Rconfiguration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula I or a salt thereof, wherein: R^(C) isNH₂; R^(N) is selected from the group consisting of H, C₁₋₃ alkyl,—C(O)R¹⁷, —C(O)C₁₋₃ alkylene-C(O)OR¹⁸, —C(O)C₁₋₃ alkylene-N(R²⁰)C(O)R¹⁹,—C(O)C₁₋₃ alkylene-NR²¹R²², —C(O)C₁₋₃ alkylene-C(O)NR²³R²⁴, and—C(O)C₁₋₃ alkylene-S(O)₂R²⁵, wherein R¹⁷ is C₁₋₆ alkyl or 5- to6-membered heteroaryl, R¹⁸ is C₁₋₃ alkyl, R¹⁹ is C₁₋₃ alkyl or C₆ aryl,each of R²⁰, R²¹, R²², R²³ and R²⁴ is H, and R²⁵ is C₆ aryl; R¹ is

wherein R⁸⁹ is Cl or hydroxyl; R⁴ is selected from the group consistingof:

-   -   (i)

-   -   wherein each of R⁹⁰ and R⁹¹ is independently selected from the        group consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, wherein the C₁₋₆ alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆ alkoxy, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆ alkoxy, and wherein        n² is 3 or 4;    -   (iii)

-   -   wherein each of R⁹⁹ and R¹⁰⁰ is independently selected from the        group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein n⁴        is 1 or 2;    -   (iv)

-   -   wherein R¹⁰³ is selected from the group consisting of C₁₋₆        alkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, and 5- to        10-membered heterocycloalkyl, wherein the C₁₋₆alkyl is        optionally substituted with one or more substituents each        independently selected from the group consisting of halogen,        hydroxy, —NO₂, and C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl, 5- to        10-membered heteroaryl, and 5- to 10-membered heterocycloalkyl        are optionally substituted with one or more substituents each        independently selected from the group consisting of halogen,        hydroxy, —NO₂, and C₁₋₆ alkoxy, and wherein n⁵ is 1 or 2;    -   (v)

-   -   wherein R¹¹⁰ is selected from the group consisting of H, C₁₋₆        alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, R¹¹¹ is        selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and        5- to 10-membered heteroaryl, wherein the C₁₋₆ alkyl of R¹¹⁰ or        R¹¹¹ is optionally substituted with one or more substituents        each independently selected from the group consisting of        halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl        and 5- to 10-membered heteroaryl of R¹⁰ or R¹¹ are optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆ alkoxy, and wherein n⁶ is 1 or 2;    -   (vi)

-   -   wherein R¹¹⁹ is selected from the group consisting of C₁₋₆alkyl,        C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the        C₁₋₆alkyl is optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, hydroxy, —NO₂, and C₁₋₆alkoxy, and        wherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are        optionally substituted with one or more substituents each        independently selected from the group consisting of halogen,        hydroxy, —NO₂, and C₁₋₆alkoxy, and wherein n⁸ is 1 or 2;    -   (viii)

-   -   wherein: each of R¹³⁴ and R¹³⁵ is independently selected from        the group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, 5- to        10-membered heteroaryl, —C(O)R¹³⁶, and —C(O)NR¹³⁷R¹³⁸, wherein        the C₁₋₆alkyl is optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆ alkoxy, and wherein        the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆alkoxy, and wherein n¹⁰ is 1 or 2, and wherein n¹¹ is 1 or        2;    -   R¹³⁶ is selected from the group consisting of C₁₋₆ alkyl, C₆₋₁₀        aryl, and 5- to 10-membered heteroaryl, wherein the C₁₋₆alkyl is        optionally substituted with one or more substituents each        independently selected from the group consisting of halogen,        —OH, —NO₂, and C₁₋₆ alkoxy, and wherein the C₆₋₁₀ aryl and 5- to        10-membered heteroaryl are optionally substituted with one or        more substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy; and    -   each of R¹³⁷ and R¹³⁸ is independently selected from the group        consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-membered        heteroaryl, wherein the C₁₋₆ alkyl is optionally substituted        with one or more substituents each independently selected from        the group consisting of halogen, —OH, —NO₂, and C₁₋₆ alkoxy, and        wherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are        optionally substituted with one or more substituents each        independently selected from the group consisting of halogen,        —OH, —NO₂, and C₁₋₆alkoxy;    -   (ix)

-   -   wherein each of R¹⁴⁴ and R¹⁴⁵ is independently selected from the        group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂,        C₁₋₆alkoxy, and 5- to 10-membered heterocycloalkyl, and wherein        the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂,        C₁₋₆alkoxy, and 5- to 10-membered heterocycloalkyl, and wherein        n¹² is 1 or 2; and    -   (xii)

-   -   wherein n¹⁵ is 1 or 2;        R⁵ is —NH₂, —NHCH₃ or —N(CH₃)₂; n¹ is 4; R⁶ is —CH(CH₃)OH; R⁸ is

wherein R¹⁵¹ is Cl or hydroxyl; each of R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, andR¹⁵ is H; L is

and chiral centre *1 is in the S configuration, chiral centre *2 is inthe S configuration, chiral centre *3 is in the S configuration, chiralcentre *4 is in the R configuration, chiral centre *5 is in the Sconfiguration, chiral centre *6 is in the S configuration, chiral centre*7 is in the R configuration, and chiral centre *8 is in the Rconfiguration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula I or a salt thereof, wherein: R^(C) isNH₂; R^(N) is selected from the group consisting of H, C₁₋₃ alkyl,—C(O)R¹⁷, —C(O)C₁₋₃ alkylene-C(O)OR¹⁸, —C(O)C₁₋₃ alkylene-N(R²⁰)C(O)R¹⁹,—C(O)C₁₋₃ alkylene-NR²¹R²², —C(O)C₁₋₃ alkylene-C(O)NR²³R²⁴, and—C(O)C₁₋₃ alkylene-S(O)₂R²⁵, wherein R¹⁷ is C₁₋₆ alkyl or 5- to6-membered heteroaryl, R¹⁸ is C₁₋₃ alkyl, R¹⁹ is C₁₋₃ alkyl or C₆ aryl,each of R²⁰, R²¹, R²², R²³ and R²⁴ is H, and R²⁵ is C₆ aryl; R¹ is

wherein R⁸⁹ is Cl or hydroxyl;R⁴ is selected from the group consisting of:

-   -   (iii)

-   -   wherein each of R⁹⁹ and R¹⁰⁰ is independently selected from the        group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein n⁴        is 1 or 2; and    -   (v)

-   -   wherein R¹¹⁰ is selected from the group consisting of H, C₁₋₆        alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, R¹¹¹ is        selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and        5- to 10-membered heteroaryl, wherein the C₁₋₆ alkyl of R¹¹⁰ or        R¹¹¹ is optionally substituted with one or more substituents        each independently selected from the group consisting of        halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl        and 5- to 10-membered heteroaryl of R¹¹⁰ or R¹¹¹ are optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆ alkoxy, and wherein n⁶ is 1 or 2;        R⁵ is —NH₂, —NHCH₃ or —N(CH₃)₂; n¹ is 4; R⁶ is —CH(CH₃)OH; R⁸ is

wherein R¹⁵¹ is Cl or hydroxyl; each of R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, andR¹⁵ is H; L is

and chiral centre *1 is in the S configuration, chiral centre *2 is inthe S configuration, chiral centre *3 is in the S configuration, chiralcentre *4 is in the R configuration, chiral centre *5 is in the Sconfiguration, chiral centre *6 is in the S configuration, chiral centre*7 is in the R configuration, and chiral centre *8 is in the Rconfiguration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula I or a salt thereof, wherein: R^(C) isNH₂; R^(N) is selected from the group consisting of H, C₁₋₃ alkyl,—C(O)R¹⁷, —C(O)C₁₋₃ alkylene-C(O)OR¹⁸, —C(O)C₁₋₃ alkylene-N(R²⁰)C(O)R¹⁹,—C(O)C₁₋₃ alkylene-NR²¹R²², —C(O)C₁₋₃ alkylene-C(O)NR²³R²⁴, and—C(O)C₁₋₃ alkylene-S(O)₂R²⁵, wherein R¹⁷ is C₁₋₆ alkyl or 5- to6-membered heteroaryl, R¹⁸ is C₁₋₃ alkyl, R¹⁹ is C₁₋₃ alkyl or C₆ aryl,each of R²⁰, R²¹, R²², R²³ and R²⁴ is H, and R²⁵ is C₆ aryl; R¹ is

wherein R⁸⁹ is Cl or hydroxyl; R⁴ is selected from the group consistingof:

-   -   (iii)

-   -   wherein each of R⁹⁹ and R¹⁰⁰ is independently selected from the        group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, and wherein n⁴ is 1 or 2; and    -   (v)

-   -   wherein R¹¹⁰ is selected from the group consisting of H, C₁₋₆        alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, and R¹¹¹ is        selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and        5- to 10-membered heteroaryl, and wherein n⁶ is 1 or 2;        R⁵ is —NH₂, —NHCH₃ or —N(CH₃)₂; n¹ is 4; R⁶ is —CH(CH₃)OH; R⁸ is

wherein R¹⁵¹ is Cl or hydroxyl; each of R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, andR¹⁵ is H; L is

and chiral centre *1 is in the S configuration, chiral centre *2 is inthe S configuration, chiral centre *3 is in the S configuration, chiralcentre *4 is in the R configuration, chiral centre *5 is in the Sconfiguration, chiral centre *6 is in the S configuration, chiral centre*7 is in the R configuration, and chiral centre *8 is in the Rconfiguration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula I or a salt thereof, wherein: R^(C) isNH₂; R^(N) is selected from the group consisting of H, C₁₋₃ alkyl,—C(O)R¹⁷, —C(O)C₁₋₃ alkylene-C(O)OR¹⁸, —C(O)C₁₋₃ alkylene-N(R²⁰)C(O)R¹⁹,—C(O)C₁₋₃ alkylene-NR²¹R²², —C(O)C₁₋₃ alkylene-C(O)NR²³R²⁴, and—C(O)C₁₋₃ alkylene-S(O)₂R²⁵, wherein R¹⁷ is C₁₋₆ alkyl or 5- to6-membered heteroaryl, R¹⁸ is C₁₋₃ alkyl, R¹⁹ is C₁₋₃ alkyl or C₆ aryl,each of R²⁰, R²¹, R²², R²³ and R²⁴ is H, and R²⁵ is C₆ aryl; R¹ is

wherein R⁸⁹ is Cl or hydroxyl; R⁴ is selected from the group consistingof: (iii)

wherein each of R⁹⁹ and R¹⁰⁰ is independently selected from the groupconsisting of H and C₁₋₆ alkyl, and wherein n⁴ is 1 or 2; and (v)

wherein R¹¹⁰ is H, and R¹¹¹ is C₆ aryl, and wherein n⁶ is 1 or 2; R⁵ is—NH₂, —NHCH₃ or —N(CH₃)₂; n¹ is 4; R⁶ is —CH(CH₃)OH; R⁸ is

wherein R¹⁵¹ is Cl or hydroxyl; each of R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, andR¹⁵ is H; L is

and chiral centre *1 is in the S configuration, chiral centre *2 is inthe S configuration, chiral centre *3 is in the S configuration, chiralcentre *4 is in the R configuration, chiral centre *5 is in the Sconfiguration, chiral centre *6 is in the S configuration, chiral centre*7 is in the R configuration, and chiral centre *8 is in the Rconfiguration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula I or a salt thereof, wherein: R^(C) isNH₂; R^(N) is selected from the group consisting of H, C₁₋₃ alkyl,—C(O)R¹⁷, —C(O)C₁₋₃ alkylene-C(O)OR¹⁸, —C(O)C₁₋₃ alkylene-N(R²⁰)C(O)R¹⁹,—C(O)C₁₋₃ alkylene-NR²¹R²², —C(O)C₁₋₃ alkylene-C(O)NR²³R²⁴, and—C(O)C₁₋₃ alkylene-S(O)₂R²⁵, wherein R¹⁷ is C₁₋₆ alkyl or 5- to6-membered heteroaryl, R¹⁸ is C₁₋₃ alkyl, R¹⁹ is C₁₋₃ alkyl or C₆ aryl,each of R²⁰, R²¹, R²², R²³ and R²⁴ is H, and R²⁵ is C₆ aryl; R¹ is

wherein R⁸⁹ is Cl or hydroxyl; R⁴ is: (iii)

wherein each of R⁹⁹ and R¹⁰⁰ is independently selected from the groupconsisting of H and C₁₋₆ alkyl, and wherein n⁴ is 1 or 2; R⁵ is —NH₂,—NHCH₃ or —N(CH₃)₂; n¹ is 4; R⁶ is —CH(CH₃)OH; R⁸ is

wherein R¹⁵¹ is Cl or hydroxyl; each of R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, andR¹⁵ is H; L is

and chiral centre *1 is in the S configuration, chiral centre *2 is inthe S configuration, chiral centre *3 is in the S configuration, chiralcentre *4 is in the R configuration, chiral centre *5 is in the Sconfiguration, chiral centre *6 is in the S configuration, chiral centre*7 is in the R configuration, and chiral centre *8 is in the Rconfiguration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula I or a salt thereof, wherein: R^(C) isNH₂; R^(N) is selected from the group consisting of H, C₁₋₃ alkyl,—C(O)R¹⁷, —C(O)C₁₋₃ alkylene-C(O)OR¹⁸, —C(O)C₁₋₃ alkylene-N(R²⁰)C(O)R¹⁹,—C(O)C₁₋₃ alkylene-NR²¹R²², —C(O)C₁₋₃ alkylene-C(O)NR²³R²⁴, and—C(O)C₁₋₃ alkylene-S(O)₂R²⁵, wherein R¹⁷ is C₁₋₆ alkyl or 5- to6-membered heteroaryl, R¹⁸ is C₁₋₃ alkyl, R¹⁹ is C₁₋₃ alkyl or C₆ aryl,each of R²⁰, R²¹, R²², R²³ and R²⁴ is H, and R²⁵ is C₆ aryl; R¹ is

wherein R⁸⁹ is Cl or hydroxyl; R⁴ is: (iii)

wherein each of R⁹⁹ and R¹⁰⁰ is H, and wherein n⁴ is 1 or 2; R⁵ is —NH₂,—NHCH₃ or —N(CH₃)₂; n¹ is 4; R⁶ is —CH(CH₃)OH; R⁸ is

wherein R¹⁵¹ is Cl or hydroxyl; each of R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, andR¹⁵ is H; L is

and chiral centre *1 is in the S configuration, chiral centre *2 is inthe S configuration, chiral centre *3 is in the S configuration, chiralcentre *4 is in the R configuration, chiral centre *5 is in the Sconfiguration, chiral centre *6 is in the S configuration, chiral centre*7 is in the R configuration, and chiral centre *8 is in the Rconfiguration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula I or a salt thereof, wherein: R^(C) isNH₂; R^(N) is selected from the group consisting of H, C₁₋₃ alkyl,—C(O)R¹⁷, —C(O)C₁₋₃ alkylene-C(O)OR¹⁸, —C(O)C₁₋₃ alkylene-N(R²⁰)C(O)R¹⁹,—C(O)C₁₋₃ alkylene-NR²¹R²², —C(O)C₁₋₃ alkylene-C(O)NR²³R²⁴, and—C(O)C₁₋₃ alkylene-S(O)₂R²⁵, wherein R¹⁷ is C₁₋₆ alkyl or 5- to6-membered heteroaryl, R¹⁸ is C₁₋₃ alkyl, R¹⁹ is C₁₋₃ alkyl or C₆ aryl,each of R²⁰, R²¹, R²², R²³ and R²⁴ is H, and R²⁵ is C₆ aryl; R¹ is

wherein R⁸⁹ is Cl or hydroxyl; R⁴ is

R⁵ is —NH₂, —NHCH₃ or —N(CH₃)₂; n¹ is 4; R⁶ is —CH(CH₃)OH; R⁸ is

wherein R¹⁵¹ is Cl or hydroxyl; each of R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, andR¹⁵ is H; L is

and chiral centre *1 is in the S configuration, chiral centre *2 is inthe S configuration, chiral centre *3 is in the S configuration, chiralcentre *4 is in the R configuration, chiral centre *5 is in the Sconfiguration, chiral centre *6 is in the S configuration, chiral centre*7 is in the R configuration, and chiral centre *8 is in the Rconfiguration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula I or a salt thereof, wherein: R^(C) isNH₂; R^(N) is selected from the group consisting of H, C₁₋₃ alkyl,—C(O)R¹⁷, —C(O)C₁₋₃ alkylene-C(O)OR¹⁸, —C(O)C₁₋₃ alkylene-N(R²⁰)C(O)R¹⁹,—C(O)C₁₋₃ alkylene-NR²¹R²², —C(O)C₁₋₃ alkylene-C(O)NR²³R²⁴, and—C(O)C₁₋₃ alkylene-S(O)₂R²⁵, wherein R¹⁷ is C₁₋₆alkyl or 5- to6-membered heteroaryl, R¹⁸ is C₁₋₃ alkyl, R¹⁹ is C₁₋₃ alkyl or C₆ aryl,each of R²⁰, R²¹, R²², R²³ and R²⁴ is H, and R²⁵ is C₆ aryl; R¹ is

wherein R⁸⁹ is Cl or hydroxyl; R⁴ is

R⁵ is —NH₂, —NHCH₃ or —N(CH₃)₂; n¹ is 4; R⁶ is —CH(CH₃)OH; R⁸ is

wherein R¹⁵¹ is Cl or hydroxyl; each of R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, andR¹⁵ is H; L is

and chiral centre *1 is in the S configuration, chiral centre *2 is inthe S configuration, chiral centre *3 is in the S configuration, chiralcentre *4 is in the R configuration, chiral centre *5 is in the Sconfiguration, chiral centre *6 is in the S configuration, chiral centre*7 is in the R configuration, and chiral centre *8 is in the Rconfiguration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula I or a salt thereof, wherein: R^(C) isNH₂; R^(N) is H; R¹ is

wherein R⁸⁹ is Cl or hydroxyl;R⁴ is selected from the group consisting of:

-   -   (i)

-   -   wherein each of R⁹⁰ and R⁹¹ is independently selected from the        group consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, wherein the C₁₋₆ alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆ alkoxy, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆ alkoxy, and wherein        n² is 3 or 4;    -   (ii)

-   -   wherein R⁹⁶ is selected from the group consisting of C₁₋₆ alkyl,        C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the        C₁₋₆alkyl is optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein        the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆ alkoxy, and wherein n³ is 3 or 4;    -   (iii)

-   -   wherein each of R⁹⁹ and R¹⁰⁰ is independently selected from the        group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein n⁴        is 1 or 2;    -   (iv)

-   -   wherein R¹⁰³ is selected from the group consisting of C₁₋₆alkyl,        C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered        heterocycloalkyl, wherein the C₁₋₆alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, hydroxy, —NO₂,        and C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl, 5- to 10-membered        heteroaryl, and 5- to 10-membered heterocycloalkyl are        optionally substituted with one or more substituents each        independently selected from the group consisting of halogen,        hydroxy, —NO₂, and C₁₋₆ alkoxy, and wherein n⁵ is 1 or 2;    -   (v)

-   -   wherein R¹¹⁰ is selected from the group consisting of H, C₁₋₆        alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, R¹¹¹ is        selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and        5- to 10-membered heteroaryl, wherein the C₁₋₆ alkyl of R¹¹⁰ or        R¹¹¹ is optionally substituted with one or more substituents        each independently selected from the group consisting of        halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl        and 5- to 10-membered heteroaryl of R¹¹⁰ or R¹¹¹ are optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆ alkoxy, and wherein n⁶ is 1 or 2;    -   (vi)

-   -   wherein R¹¹⁹ is selected from the group consisting of C₁₋₆alkyl,        C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the        C₁₋₆alkyl is optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, hydroxy, —NO₂, and C₁₋₆alkoxy, and        wherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are        optionally substituted with one or more substituents each        independently selected from the group consisting of halogen,        hydroxy, —NO₂, and C₁₋₆alkoxy, and wherein n⁸ is 1 or 2;    -   (vii)

-   -   wherein each of R¹²⁶ and R¹²⁷ is independently selected from the        group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein n⁹        is 1 or 2;    -   (viii)

-   -   wherein: each of R¹³⁴ and R¹³⁵ is independently selected from        the group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, 5- to        10-membered heteroaryl, —C(O)R¹³⁶, and —C(O)NR¹³⁷R¹³⁸, wherein        the C₁₋₆alkyl is optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆ alkoxy, and wherein        the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆alkoxy, and wherein n¹⁰ is 1 or 2, and wherein n¹¹ is 1 or        2;    -   R¹³⁶ is selected from the group consisting of C₁₋₆ alkyl, C₆₋₁₀        aryl, and 5- to 10-membered heteroaryl, wherein the C₁₋₆alkyl is        optionally substituted with one or more substituents each        independently selected from the group consisting of halogen,        —OH, —NO₂, and C₁₋₆ alkoxy, and wherein the C₆₋₁₀ aryl and 5- to        10-membered heteroaryl are optionally substituted with one or        more substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy; and    -   each of R¹³⁷ and R¹³⁸ is independently selected from the group        consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-membered        heteroaryl, wherein the C₁₋₆ alkyl is optionally substituted        with one or more substituents each independently selected from        the group consisting of halogen, —OH, —NO₂, and C₁₋₆ alkoxy, and        wherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are        optionally substituted with one or more substituents each        independently selected from the group consisting of halogen,        —OH, —NO₂, and C₁₋₆alkoxy;    -   (ix)

-   -   wherein each of R¹⁴⁴ and R¹⁴⁵ is independently selected from the        group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂,        C₁₋₆alkoxy, and 5- to 10-membered heterocycloalkyl, and wherein        the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂,        C₁₋₆alkoxy, and 5- to 10-membered heterocycloalkyl, and wherein        n¹² is 1 or 2;    -   (x)

-   -   wherein R¹⁴⁶ is selected from the group consisting of C₂₋₆        alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the        C₂₋₆ alkyl is optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, C₁₋₆ alkoxy, and 5- to        10-membered heterocycloalkyl, and wherein the C₆₋₁₀ aryl and 5-        to 10-membered heteroaryl are optionally substituted with one or        more substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, C₁₋₆alkoxy, and 5- to        10-membered heterocycloalkyl, and wherein n¹³ is 1 or 2;    -   (xi)

-   -   wherein R¹⁴⁸ is H or CH₃, R¹⁴⁹ is H or C₁₋₆ alkyl optionally        substituted with one or more substituents each independently        selected from the group consisting of hydroxyl, —COOH, —NH₂,        —C(O)NH₂, and —N(H)C(O)NH₂, and R¹⁵⁰ is H, CH₃ or acetyl, and        wherein n¹⁴ is 1 or 2; and    -   (xii)

-   -   wherein n¹⁵ is 1 or 2;        R⁵ is —NH₂, —NHCH₃ or —N(CH₃)₂; n¹ is 4; R⁶ is —CH(CH₃)OH; R⁸ is

wherein R¹⁵¹ is Cl or hydroxyl; each of R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, andR¹⁵ is H; L is

and chiral centre *1 is in the S configuration, chiral centre *2 is inthe S configuration, chiral centre *3 is in the S configuration, chiralcentre *4 is in the R configuration, chiral centre *5 is in the Sconfiguration, chiral centre *6 is in the S configuration, chiral centre*7 is in the R configuration, and chiral centre *8 is in the Rconfiguration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula I or a salt thereof, wherein: R^(C) isNH₂; R^(N) is H; R¹ is I; R³ is

wherein R⁸⁹ is Cl or hydroxyl;R⁴ is selected from the group consisting of:

-   -   (i)

-   -   wherein each of R⁹⁰ and R⁹¹ is independently selected from the        group consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, wherein the C₁₋₆ alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆ alkoxy, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆ alkoxy, and wherein        n² is 3 or 4;    -   (iii)

-   -   wherein each of R⁹⁹ and R¹⁰⁰ is independently selected from the        group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein n⁴        is 1 or 2;    -   (iv)

-   -   wherein R¹⁰³ is selected from the group consisting of C₁₋₆alkyl,        C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered        heterocycloalkyl, wherein the C₁₋₆alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, hydroxy, —NO₂,        and C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl, 5- to 10-membered        heteroaryl, and 5- to 10-membered heterocycloalkyl are        optionally substituted with one or more substituents each        independently selected from the group consisting of halogen,        hydroxy, —NO₂, and C₁₋₆ alkoxy, and wherein n⁵ is 1 or 2;    -   (v)

-   -   wherein R¹¹⁰ is selected from the group consisting of H, C₁₋₆        alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, R¹¹¹ is        selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and        5- to 10-membered heteroaryl, wherein the C₁₋₆ alkyl of R¹¹⁰ or        R¹¹¹ is optionally substituted with one or more substituents        each independently selected from the group consisting of        halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl        and 5- to 10-membered heteroaryl of R¹⁰ or R¹¹ are optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆ alkoxy, and wherein n⁶ is 1 or 2;    -   (vi)

-   -   wherein R¹¹⁹ is selected from the group consisting of C₁₋₆alkyl,        C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the        C₁₋₆alkyl is optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, hydroxy, —NO₂, and C₁₋₆alkoxy, and        wherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are        optionally substituted with one or more substituents each        independently selected from the group consisting of halogen,        hydroxy, —NO₂, and C₁₋₆alkoxy, and wherein n⁸ is 1 or 2;    -   (viii)

-   -   wherein: each of R¹³⁴ and R¹³⁵ is independently selected from        the group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, 5- to        10-membered heteroaryl, —C(O)R¹³⁶, and —C(O)NR¹³⁷R¹³⁸, wherein        the C₁₋₆alkyl is optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆ alkoxy, and wherein        the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆alkoxy, and wherein n¹⁰ is 1 or 2, and wherein n¹¹ is 1 or        2;    -   R¹³⁶ is selected from the group consisting of C₁₋₆ alkyl, C₆₋₁₀        aryl, and 5- to 10-membered heteroaryl, wherein the C₁₋₆alkyl is        optionally substituted with one or more substituents each        independently selected from the group consisting of halogen,        —OH, —NO₂, and C₁₋₆ alkoxy, and wherein the C₆₋₁₀ aryl and 5- to        10-membered heteroaryl are optionally substituted with one or        more substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy; and    -   each of R¹³⁷ and R¹³⁸ is independently selected from the group        consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-membered        heteroaryl, wherein the C₁₋₆ alkyl is optionally substituted        with one or more substituents each independently selected from        the group consisting of halogen, —OH, —NO₂, and C₁₋₆ alkoxy, and        wherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are        optionally substituted with one or more substituents each        independently selected from the group consisting of halogen,        —OH, —NO₂, and C₁₋₆alkoxy;    -   (ix)

-   -   wherein each of R¹⁴⁴ and R¹⁴⁵ is independently selected from the        group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂,        C₁₋₆alkoxy, and 5- to 10-membered heterocycloalkyl, and wherein        the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂,        C₁₋₆alkoxy, and 5- to 10-membered heterocycloalkyl, and wherein        n¹² is 1 or 2; and    -   (xii)

-   -   wherein n¹⁵ is 1 or 2;        R⁵ is —NH₂, —NHCH₃ or —N(CH₃)₂; n¹ is 4; R⁶ is —CH(CH₃)OH; R⁸ is

wherein R¹⁵¹ is Cl or hydroxyl; each of R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, andR¹⁵ is H; L is

and chiral centre *1 is in the S configuration, chiral centre *2 is inthe S configuration, chiral centre *3 is in the S configuration, chiralcentre *4 is in the R configuration, chiral centre *5 is in the Sconfiguration, chiral centre *6 is in the S configuration, chiral centre*7 is in the R configuration, and chiral centre *8 is in the Rconfiguration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula I or a salt thereof, wherein: R^(C) isNH₂; R^(N) is H; R¹ is

wherein R⁸⁹ is Cl or hydroxyl;R⁴ is selected from the group consisting of:

-   -   (iii)

-   -   wherein each of R⁹⁹ and R¹⁰⁰ is independently selected from the        group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein n⁴        is 1 or 2; and    -   (v)

-   -   wherein R¹¹⁰ is selected from the group consisting of H, C₁₋₆        alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, R¹¹¹ is        selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and        5- to 10-membered heteroaryl, wherein the C₁₋₆ alkyl of R¹¹⁰ or        R¹¹¹ is optionally substituted with one or more substituents        each independently selected from the group consisting of        halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl        and 5- to 10-membered heteroaryl of R¹⁰ or R¹¹ are optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆ alkoxy, and wherein n⁶ is 1 or 2;        R⁵ is —NH₂, —NHCH₃ or —N(CH₃)₂; n¹ is 4; R⁶ is —CH(CH₃)OH; R⁸ is

wherein R¹⁵¹ is Cl or hydroxyl; each of R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, andR¹⁵ is H; L is

and chiral centre *1 is in the S configuration, chiral centre *2 is inthe S configuration, chiral centre *3 is in the S configuration, chiralcentre *4 is in the R configuration, chiral centre *5 is in the Sconfiguration, chiral centre *6 is in the S configuration, chiral centre*7 is in the R configuration, and chiral centre *8 is in the Rconfiguration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula I or a salt thereof, wherein: R^(C) isNH₂; R^(N) is H; R¹ is

wherein R⁸⁹ is Cl or hydroxyl; R⁴ is selected from the group consistingof: (iii)

wherein each of R⁹⁹ and R¹⁰⁰ is independently selected from the groupconsisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl, and wherein n⁴ is 1 or 2; and (v)

wherein R¹¹⁰ is selected from the group consisting of H, C₁₋₆ alkyl,C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, and R¹¹¹ is selected fromthe group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl, and wherein n⁶ is 1 or 2; R⁵ is —NH₂, —NHCH₃ or —N(CH₃)₂; n¹is 4; R⁶ is —CH(CH₃)OH; R⁸ is

wherein R¹⁵¹ is Cl or hydroxyl; each of R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, andR¹⁵ is H; L is

and chiral centre *1 is in the S configuration, chiral centre *2 is inthe S configuration, chiral centre *3 is in the S configuration, chiralcentre *4 is in the R configuration, chiral centre *5 is in the Sconfiguration, chiral centre *6 is in the S configuration, chiral centre*7 is in the R configuration, and chiral centre *8 is in the Rconfiguration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula I or a salt thereof, wherein: R^(C) isNH₂; R^(N) is H; R¹ is; R³ is

wherein R⁸⁹ is Cl or hydroxyl;R⁴ is selected from the group consisting of: (iii)

wherein each of R⁹⁹ and R¹⁰⁰ is independently selected from the groupconsisting of H and C₁₋₆ alkyl, and wherein n⁴ is 1 or 2; and (v)

wherein R¹¹⁰ is H, and R¹¹¹ is C₆ aryl, and wherein n⁶ is 1 or 2; R⁵ is—NH₂, —NHCH₃ or —N(CH₃)₂; n¹ is 4; R⁶ is —CH(CH₃)OH; R⁸ is

wherein R¹⁵¹ is Cl or hydroxyl; each of R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, andR¹⁵ is H; L is

and chiral centre *1 is in the S configuration, chiral centre *2 is inthe S configuration, chiral centre *3 is in the S configuration, chiralcentre *4 is in the R configuration, chiral centre *5 is in the Sconfiguration, chiral centre *6 is in the S configuration, chiral centre*7 is in the R configuration, and chiral centre *8 is in the Rconfiguration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula I or a salt thereof, wherein: R^(C) isNH₂; R^(N) is H; R¹ is

wherein R⁸⁹ is Cl or hydroxyl; R⁴ is: (iii)

wherein each of R⁹⁹ and R¹⁰⁰ is independently selected from the groupconsisting of H and C₁₋₆ alkyl, and wherein n⁴ is 1 or 2; R⁵ is —NH₂,—NHCH₃ or —N(CH₃)₂; n¹ is 4; R⁶ is —CH(CH₃)OH; R⁸ is

wherein R¹⁵¹ is Cl or hydroxyl; each of R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, andR¹⁵ is H; L is

and chiral centre *1 is in the S configuration, chiral centre *2 is inthe S configuration, chiral centre *3 is in the S configuration, chiralcentre *4 is in the R configuration, chiral centre *5 is in the Sconfiguration, chiral centre *6 is in the S configuration, chiral centre*7 is in the R configuration, and chiral centre *8 is in the Rconfiguration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula I or a salt thereof, wherein: R^(C) isNH₂; R^(N) is H; R¹ is

wherein R⁸⁹ is Cl or hydroxyl; R⁴ is: (iii)

wherein each of R⁹⁹ and R¹⁰⁰ is H, and wherein n⁴ is 1 or 2; R⁵ is —NH₂,—NHCH₃ or —N(CH₃)₂; n¹ is 4; R⁶ is —CH(CH₃)OH; R⁸ is

wherein R¹⁵¹ is Cl or hydroxyl; each of R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, andR¹⁵ is H; L is

and chiral centre *1 is in the S configuration, chiral centre *2 is inthe S configuration, chiral centre *3 is in the S configuration, chiralcentre *4 is in the R configuration, chiral centre *5 is in the Sconfiguration, chiral centre *6 is in the S configuration, chiral centre*7 is in the R configuration, and chiral centre *8 is in the Rconfiguration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula I or a salt thereof, wherein: R^(C) isNH₂; R^(N) is H; R¹ is

wherein R⁸⁹ is Cl or hydroxyl; R⁴ is

R⁵ is —NH₂, —NHCH₃ or —N(CH₃)₂; n¹ is 4; R⁶ is —CH(CH₃)OH; R⁸ is

wherein R¹⁵¹ is Cl or hydroxyl; each of R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, andR¹⁵ is H; L is

and chiral centre *1 is in the S configuration, chiral centre *2 is inthe S configuration, chiral centre *3 is in the S configuration, chiralcentre *4 is in the R configuration, chiral centre *5 is in the Sconfiguration, chiral centre *6 is in the S configuration, chiral centre*7 is in the R configuration, and chiral centre *8 is in the Rconfiguration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula I or a salt thereof, wherein: R^(C) isNH₂; R^(N) is H; R¹ is

wherein R⁸⁹ is Cl or hydroxyl; R⁴ is

R⁵ is —NH₂—NHCH₃ or —N(CH₃)₂; n¹ is 4; R⁶ is —CH(CH₃)OH; R⁸ is

wherein R¹⁵¹ is Cl or hydroxyl; each of R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, andR¹⁵ is H; L is

and chiral centre *1 is in the S configuration, chiral centre *2 is inthe S configuration, chiral centre *3 is in the S configuration, chiralcentre *4 is in the R configuration, chiral centre *5 is in the Sconfiguration, chiral centre *6 is in the S configuration, chiral centre*7 is in the R configuration, and chiral centre *8 is in the Rconfiguration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula I or a salt thereof, wherein: R^(C) isNH₂; R^(N) is H; R¹ is

R⁴ is selected from the group consisting of:

-   -   (i)

-   -   wherein each of R⁹⁰ and R⁹¹ is independently selected from the        group consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, wherein the C₁₋₆ alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆ alkoxy, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆ alkoxy, and wherein        n² is 3 or 4;    -   (ii)

-   -   wherein R⁹⁶ is selected from the group consisting of C₁₋₆ alkyl,        C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the        C₁₋₆alkyl is optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein        the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆ alkoxy, and wherein n³ is 3 or 4;    -   (iii)

-   -   wherein each of R⁹⁹ and R¹⁰⁰ is independently selected from the        group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein n⁴        is 1 or 2;    -   (iv)

-   -   wherein R¹⁰³ is selected from the group consisting of C₁₋₆alkyl,        C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered        heterocycloalkyl, wherein the C₁₋₆alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, hydroxy, —NO₂,        and C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl, 5- to 10-membered        heteroaryl, and 5- to 10-membered heterocycloalkyl are        optionally substituted with one or more substituents each        independently selected from the group consisting of halogen,        hydroxy, —NO₂, and C₁₋₆ alkoxy, and wherein n⁵ is 1 or 2;    -   (v)

-   -   wherein R¹¹⁰ is selected from the group consisting of H, C₁₋₆        alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, R¹¹¹ is        selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and        5- to 10-membered heteroaryl, wherein the C₁₋₆ alkyl of R¹¹⁰ or        R¹¹¹ is optionally substituted with one or more substituents        each independently selected from the group consisting of        halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl        and 5- to 10-membered heteroaryl of R¹⁰ or R¹¹ are optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆ alkoxy, and wherein n⁶ is 1 or 2;    -   (vi)

-   -   wherein R¹¹⁹ is selected from the group consisting of C₁₋₆alkyl,        C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the        C₁₋₆alkyl is optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, hydroxy, —NO₂, and C₁₋₆alkoxy, and        wherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are        optionally substituted with one or more substituents each        independently selected from the group consisting of halogen,        hydroxy, —NO₂, and C₁₋₆alkoxy, and wherein n⁸ is 1 or 2;    -   (vii)

-   -   wherein each of R¹²⁶ and R¹²⁷ is independently selected from the        group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein n⁹        is 1 or 2;    -   (viii)

-   -   wherein: each of R¹³⁴ and R¹³⁵ is independently selected from        the group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, 5- to        10-membered heteroaryl, —C(O)R¹³⁶, and —C(O)NR¹³⁷R¹³⁸, wherein        the C₁₋₆alkyl is optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆ alkoxy, and wherein        the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆alkoxy, and wherein n¹⁰ is 1 or 2, and wherein n¹¹ is 1 or        2;    -   R¹³⁶ is selected from the group consisting of C₁₋₆ alkyl, C₆₋₁₀        aryl, and 5- to 10-membered heteroaryl, wherein the C₁₋₆alkyl is        optionally substituted with one or more substituents each        independently selected from the group consisting of halogen,        —OH, —NO₂, and C₁₋₆ alkoxy, and wherein the C₆₋₁₀ aryl and 5- to        10-membered heteroaryl are optionally substituted with one or        more substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy; and    -   each of R¹³⁷ and R¹³⁸ is independently selected from the group        consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-membered        heteroaryl, wherein the C₁₋₆ alkyl is optionally substituted        with one or more substituents each independently selected from        the group consisting of halogen, —OH, —NO₂, and C₁₋₆ alkoxy, and        wherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are        optionally substituted with one or more substituents each        independently selected from the group consisting of halogen,        —OH, —NO₂, and C₁₋₆alkoxy;    -   (ix)

-   -   wherein each of R¹⁴⁴ and R¹⁴⁵ is independently selected from the        group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂,        C₁₋₆alkoxy, and 5- to 10-membered heterocycloalkyl, and wherein        the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂,        C₁₋₆alkoxy, and 5- to 10-membered heterocycloalkyl, and wherein        n¹² is 1 or 2;    -   (x)

-   -   wherein R¹⁴⁶ is selected from the group consisting of C₂₋₆        alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the        C₂₋₆ alkyl is optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, C₁₋₆ alkoxy, and 5- to        10-membered heterocycloalkyl, and wherein the C₆₋₁₀ aryl and 5-        to 10-membered heteroaryl are optionally substituted with one or        more substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, C₁₋₆alkoxy, and 5- to        10-membered heterocycloalkyl, and wherein n¹³ is 1 or 2;    -   (xi)

-   -   wherein R¹⁴⁸ is H or CH₃, R¹⁴⁹ is H or C₁₋₆ alkyl optionally        substituted with one or more substituents each independently        selected from the group consisting of hydroxyl, —COOH, —NH₂,        —C(O)NH₂, and —N(H)C(O)NH₂, and R¹⁵⁰ is H, CH₃ or acetyl, and        wherein n¹⁴ is 1 or 2; and    -   (xii)

wherein n¹⁵ is 1 or 2;R⁵ is —NH₂, —NHCH₃ or —N(CH₃)₂; n¹ is 4; R⁶ is —CH(CH₃)OH; R⁸ is

each of R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, and R¹⁵ is H; L is

and chiral centre *1 is in the S configuration, chiral centre *2 is inthe S configuration, chiral centre *3 is in the S configuration, chiralcentre *4 is in the R configuration, chiral centre *5 is in the Sconfiguration, chiral centre *6 is in the S configuration, chiral centre*7 is in the R configuration, and chiral centre *8 is in the Rconfiguration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula I or a salt thereof, wherein: R^(C) isNH₂; R^(N) is H; R¹ is

R⁴ is selected from the group consisting of:

-   -   (i)

wherein each of R⁹⁰ and R⁹¹ is independently selected from the groupconsisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl, wherein the C₁₋₆ alkyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen, —OH, —NO₂, and C₁₋₆ alkoxy, and wherein the C₆₋₁₀ aryl and5- to 10-membered heteroaryl are optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen, —OH, —NO₂, and C₁₋₆ alkoxy, and wherein n² is 3 or 4;

-   -   (iii)

-   -   wherein each of R⁹⁹ and R¹⁰⁰ is independently selected from the        group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein n⁴        is 1 or 2;    -   (iv)

-   -   wherein R¹⁰³ is selected from the group consisting of C₁₋₆alkyl,        C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered        heterocycloalkyl, wherein the C₁₋₆alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, hydroxy, —NO₂,        and C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl, 5- to 10-membered        heteroaryl, and 5- to 10-membered heterocycloalkyl are        optionally substituted with one or more substituents each        independently selected from the group consisting of halogen,        hydroxy, —NO₂, and C₁₋₆ alkoxy, and wherein n⁵ is 1 or 2;    -   (v)

-   -   wherein R¹¹⁰ is selected from the group consisting of H, C₁₋₆        alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, R¹¹¹ is        selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and        5- to 10-membered heteroaryl, wherein the C₁₋₆ alkyl of R¹¹⁰ or        R¹¹¹ is optionally substituted with one or more substituents        each independently selected from the group consisting of        halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl        and 5- to 10-membered heteroaryl of R¹⁰ or R¹¹ are optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆ alkoxy, and wherein n⁶ is 1 or 2;    -   (vi)

-   -   wherein R¹¹⁹ is selected from the group consisting of C₁₋₆alkyl,        C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the        C₁₋₆alkyl is optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, hydroxy, —NO₂, and C₁₋₆alkoxy, and        wherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are        optionally substituted with one or more substituents each        independently selected from the group consisting of halogen,        hydroxy, —NO₂, and C₁₋₆alkoxy, and wherein n⁸ is 1 or 2;    -   (viii)

-   -   wherein: each of R¹³⁴ and R¹³⁵ is independently selected from        the group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, 5- to        10-membered heteroaryl, —C(O)R¹³⁶, and —C(O)NR¹³²R¹³⁸, wherein        the C₁₋₆alkyl is optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆ alkoxy, and wherein        the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆alkoxy, and wherein n¹⁰ is 1 or 2, and wherein n¹¹ is 1 or        2;    -   R¹³⁶ is selected from the group consisting of C₁₋₆ alkyl, C₆₋₁₀        aryl, and 5- to 10-membered heteroaryl, wherein the C₁₋₆alkyl is        optionally substituted with one or more substituents each        independently selected from the group consisting of halogen,        —OH, —NO₂, and C₁₋₆ alkoxy, and wherein the C₆₋₁₀ aryl and 5- to        10-membered heteroaryl are optionally substituted with one or        more substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy; and each of        R¹³⁷ and R¹³⁸ is independently selected from the group        consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-membered        heteroaryl, wherein the C₁₋₆ alkyl is optionally substituted        with one or more substituents each independently selected from        the group consisting of halogen, —OH, —NO₂, and C₁₋₆ alkoxy, and        wherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are        optionally substituted with one or more substituents each        independently selected from the group consisting of halogen,        —OH, —NO₂, and C₁₋₆alkoxy;    -   (ix)

-   -   wherein each of R¹⁴⁴ and R¹⁴⁵ is independently selected from the        group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂,        C₁₋₆alkoxy, and 5- to 10-membered heterocycloalkyl, and wherein        the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂,        C₁₋₆alkoxy, and 5- to 10-membered heterocycloalkyl, and wherein        n¹² is 1 or 2; and    -   (xii)

-   -   wherein n¹⁵ is 1 or 2;        R⁵ is —NH₂, —NHCH₃ or —N(CH₃)₂; n¹ is 4; R⁶ is —CH(CH₃)OH; R⁸ is

each of R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, and R¹⁵ is H; L is

and chiral centre *1 is in the S configuration, chiral centre *2 is inthe S configuration, chiral centre *3 is in the S configuration, chiralcentre *4 is in the R configuration, chiral centre *5 is in the Sconfiguration, chiral centre *6 is in the S configuration, chiral centre*7 is in the R configuration, and chiral centre *8 is in the Rconfiguration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula I or a salt thereof, wherein: R^(C) isNH₂; R^(N) is H; R¹ is

R⁴ is selected from the group consisting of:

-   -   (iii)

wherein each of R⁹⁹ and R¹⁰⁰ is independently selected from the groupconsisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl, wherein the C₁₋₆alkyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl and 5-to 10-membered heteroaryl are optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein n⁴ is 1 or 2; and

-   -   (v)

-   -   wherein R¹¹⁰ is selected from the group consisting of H, C₁₋₆        alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, R¹¹¹ is        selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and        5- to 10-membered heteroaryl, wherein the C₁₋₆ alkyl of R¹¹⁰ or        R¹¹¹ is optionally substituted with one or more substituents        each independently selected from the group consisting of        halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl        and 5- to 10-membered heteroaryl of R¹⁰ or R¹¹ are optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆ alkoxy, and wherein n⁶ is 1 or 2;        R⁵ is —NH₂, —NHCH₃ or —N(CH₃)₂; n¹ is 4; R⁶ is —CH(CH₃)OH; R⁸ is

each of R⁹, R¹⁰, R¹¹, R⁹, R¹³, R¹⁴, and R¹⁵ is H; L is

and chiral centre *1 is in the S configuration, chiral centre *2 is inthe S configuration, chiral centre *3 is in the S configuration, chiralcentre *4 is in the R configuration, chiral centre *5 is in the Sconfiguration, chiral centre *6 is in the S configuration, chiral centre*7 is in the R configuration, and chiral centre *8 is in the Rconfiguration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula I or a salt thereof, wherein: R^(C) isNH₂; R^(N) is H; R¹ is, I; R³ is

is selected from the group consisting of: (iii)

wherein each of R⁹⁹ and R¹⁰⁰ is independently selected from the groupconsisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl, and wherein n⁴ is 1 or 2; and (v)

wherein R¹¹⁰ is selected from the group consisting of H, C₁₋₆alkyl,C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, and R¹¹¹ is selected fromthe group consisting of C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl, and wherein n⁶ is 1 or 2; R⁵ is —NH₂, —NHCH₃ or —N(CH₃)₂; n¹is 4; R⁶ is —CH(CH₃)OH; R⁸ is

each of R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, and R¹⁵ is H; L is

and chiral centre *1 is in the S configuration, chiral centre *2 is inthe S configuration, chiral centre *3 is in the S configuration, chiralcentre *4 is in the R configuration, chiral centre *5 is in the Sconfiguration, chiral centre *6 is in the S configuration, chiral centre*7 is in the R configuration, and chiral centre *8 is in the Rconfiguration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula I or a salt thereof, wherein: R^(C) isNH₂; R^(N) is H; R¹ is

is selected from the group consisting of: (iii)

wherein each of R⁹⁹ and R¹⁰⁰ is independently selected from the groupconsisting of H and C₁₋₆ alkyl, and wherein n⁴ is 1 or 2; and (v)

wherein R¹¹⁰ is H, and R¹¹¹ is C₆ aryl, and wherein n⁶ is 1 or 2; R⁵ is—NH₂, —NHCH₃ or —N(CH₃)₂; n¹ is 4; R⁶ is —CH(CH₃)OH; R⁸ is

each of R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, and R¹⁵ is H; L is

and chiral centre *1 is in the S configuration, chiral centre *2 is inthe S configuration, chiral centre *3 is in the S configuration, chiralcentre *4 is in the R configuration, chiral centre *5 is in the Sconfiguration, chiral centre *6 is in the S configuration, chiral centre*7 is in the R configuration, and chiral centre *8 is in the Rconfiguration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula I or a salt thereof, wherein: R^(C) isNH₂; R^(N) is H; R¹ is

R⁴ is: (iii)

wherein each of R⁹⁹ and R¹⁰⁰ is independently selected from the groupconsisting of H and C₁₋₆alkyl, and wherein n⁴ is 1 or 2; R⁵ is —NH₂,—NHCH₃ or —N(CH₃)₂; n¹ is 4; R⁶ is —CH(CH₃)OH; R⁸ is

each of R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, and R¹⁵ is H; L is

and chiral centre *1 is in the S configuration, chiral centre *2 is inthe S configuration, chiral centre *3 is in the S configuration, chiralcentre *4 is in the R configuration, chiral centre *5 is in the Sconfiguration, chiral centre *6 is in the S configuration, chiral centre*7 is in the R configuration, and chiral centre *8 is in the Rconfiguration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula I or a salt thereof, wherein: R^(C) isNH₂; R^(N) is H; R is

R⁴ is: (iii)

wherein each of R⁹⁹ and R¹⁰⁰ is H, and wherein n⁴ is 1 or 2; R⁵ is —NH₂,—NHCH₃ or —N(CH₃)₂; n¹ is 4; R⁶ is —CH(CH₃)OH; R⁸ is

each of R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, and R¹⁵ is H; L is

and chiral centre *1 is in the S configuration, chiral centre *2 is inthe S configuration, chiral centre *3 is in the S configuration, chiralcentre *4 is in the R configuration, chiral centre *5 is in the Sconfiguration, chiral centre *6 is in the S configuration, chiral centre*7 is in the R configuration, and chiral centre *8 is in the Rconfiguration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula I or a salt thereof, wherein: R^(C) isNH₂; R^(N) is H; R¹ is

R⁵ is —NH₂, —NHCH₃ or —N(CH₃)₂; n¹ is 4; R⁶ is —CH(CH₃)OH; R⁸ is

each of R⁹, R¹⁰, R¹¹, R¹², R¹³, R⁴, and R¹⁵ is H; L is

and chiral centre *1 is in the S configuration, chiral centre *2 is inthe S configuration, chiral centre *3 is in the S configuration, chiralcentre *4 is in the R configuration, chiral centre *5 is in the Sconfiguration, chiral centre *6 is in the S configuration, chiral centre*7 is in the R configuration, and chiral centre *8 is in the Rconfiguration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula I or a salt thereof, wherein: R^(C) isNH₂; R^(N) is H; R¹ is

R⁵ is —NH₂, —NHCH₃ or —N(CH₃)₂; n¹ is 4; R⁶ is —CH(CH₃)OH; R⁸ is

each of R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, and R¹⁵ is H; L is

and chiral centre *1 is in the S configuration, chiral centre *2 is inthe S configuration, chiral centre *3 is in the S configuration, chiralcentre *4 is in the R configuration, chiral centre *5 is in the Sconfiguration, chiral centre *6 is in the S configuration, chiral centre*7 is in the R configuration, and chiral centre *8 is in the Rconfiguration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula I or a salt thereof, wherein: R^(C) isNH₂; R^(N) is H; R¹ is

R⁴ is selected from the group consisting of:

-   -   (i)

-   -   wherein each of R⁹⁰ and R⁹¹ is independently selected from the        group consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, wherein the C₁₋₆ alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆ alkoxy, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆ alkoxy, and wherein        n² is 3 or 4;    -   (ii)

-   -   wherein R⁹⁶ is selected from the group consisting of C₁₋₆ alkyl,        C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the        C₁₋₆alkyl is optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein        the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆ alkoxy, and wherein n³ is 3 or 4;    -   (iii)

-   -   wherein each of R⁹⁹ and R¹⁰⁰ is independently selected from the        group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein n⁴        is 1 or 2;    -   (iv)

-   -   wherein R¹⁰³ is selected from the group consisting of C₁₋₆alkyl,        C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered        heterocycloalkyl, wherein the C₁₋₆alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, hydroxy, —NO₂,        and C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl, 5- to 10-membered        heteroaryl, and 5- to 10-membered heterocycloalkyl are        optionally substituted with one or more substituents each        independently selected from the group consisting of halogen,        hydroxy, —NO₂, and C₁₋₆ alkoxy, and wherein n⁵ is 1 or 2;    -   (v)

-   -   wherein R¹⁰ is selected from the group consisting of H, C₁₋₆        alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, R¹¹¹ is        selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and        5- to 10-membered heteroaryl, wherein the C₁₋₆ alkyl of R¹¹⁰ or        R¹¹¹ is optionally substituted with one or more substituents        each independently selected from the group consisting of        halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl        and 5- to 10-membered heteroaryl of R¹¹⁰ or R¹¹¹ are optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆ alkoxy, and wherein n⁶ is 1 or 2;    -   (vi)

-   -   wherein R¹¹⁹ is selected from the group consisting of C₁₋₆alkyl,        C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the        C₁₋₆alkyl is optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, hydroxy, —NO₂, and C₁₋₆alkoxy, and        wherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are        optionally substituted with one or more substituents each        independently selected from the group consisting of halogen,        hydroxy, —NO₂, and C₁₋₆alkoxy, and wherein n⁸ is 1 or 2;    -   (vii)

-   -   wherein each of R¹²⁶ and R¹²⁷ is independently selected from the        group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein n⁹        is 1 or 2;    -   (viii)

-   -   wherein: each of R¹³⁴ and R¹³⁵ is independently selected from        the group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, 5- to        10-membered heteroaryl, —C(O)R¹¹⁶, and —C(O)NR¹³⁷R¹³⁸, wherein        the C₁₋₆alkyl is optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆ alkoxy, and wherein        the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆alkoxy, and wherein n¹⁰ is 1 or 2, and wherein n¹¹ is 1 or        2;    -   R¹³⁶ is selected from the group consisting of C₁₋₆ alkyl, C₆₋₁₀        aryl, and 5- to 10-membered heteroaryl, wherein the C₁₋₆alkyl is        optionally substituted with one or more substituents each        independently selected from the group consisting of halogen,        —OH, —NO₂, and C₁₋₆ alkoxy, and wherein the C₆₋₁₀ aryl and 5- to        10-membered heteroaryl are optionally substituted with one or        more substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy; and    -   each of R¹³⁷ and R¹³⁸ is independently selected from the group        consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-membered        heteroaryl, wherein the C₁₋₆ alkyl is optionally substituted        with one or more substituents each independently selected from        the group consisting of halogen, —OH, —NO₂, and C₁₋₆ alkoxy, and        wherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are        optionally substituted with one or more substituents each        independently selected from the group consisting of halogen,        —OH, —NO₂, and C₁₋₆alkoxy;    -   (ix)

-   -   wherein each of R¹⁴⁴ and R¹⁴⁵ is independently selected from the        group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂,        C₁₋₆alkoxy, and 5- to 10-membered heterocycloalkyl, and wherein        the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂,        C₁₋₆alkoxy, and 5- to 10-membered heterocycloalkyl, and wherein        n¹² is 1 or 2;    -   (x)

-   -   wherein R¹⁴⁶ is selected from the group consisting of C₂₋₆        alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the        C₂₋₆ alkyl is optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, C₁₋₆ alkoxy, and 5- to        10-membered heterocycloalkyl, and wherein the C₆₋₁₀ aryl and 5-        to 10-membered heteroaryl are optionally substituted with one or        more substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, C₁₋₆alkoxy, and 5- to        10-membered heterocycloalkyl, and wherein n¹³ is 1 or 2;    -   (xi)

-   -   wherein R¹⁴⁸ is H or CH₃, R¹⁴⁹ is H or C₁₋₆ alkyl optionally        substituted with one or more substituents each independently        selected from the group consisting of hydroxyl, —COOH, —NH₂,        —C(O)NH₂, and —N(H)C(O)NH₂, and R¹⁵⁰ is H, CH₃ or acetyl, and        wherein n¹⁴ is 1 or 2; and    -   (xii)

-   -   wherein n¹⁵ is 1 or 2;        R⁵ is —NH₂ or —NHCH₃; n¹ is 4; R⁶ is —CH(CH₃)OH;

each of R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, and R¹⁵ is H; L is

and chiral centre *1 is in the S configuration, chiral centre *2 is inthe S configuration, chiral centre *3 is in the S configuration, chiralcentre *4 is in the R configuration, chiral centre *5 is in the Sconfiguration, chiral centre *6 is in the S configuration, chiral centre*7 is in the R configuration, and chiral centre *8 is in the Rconfiguration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula I or a salt thereof, wherein: R^(C) isNH₂; R^(N) is H;

R⁴ is selected from the group consisting of:

-   -   (i)

-   -   wherein each of R⁹⁰ and R⁹¹ is independently selected from the        group consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, wherein the C₁₋₆ alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆ alkoxy, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆ alkoxy, and wherein        n² is 3 or 4;    -   (iii)

-   -   wherein each of R⁹⁹ and R¹⁰⁰ is independently selected from the        group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein n⁴        is 1 or 2;    -   (iv)

-   -   wherein R¹⁰³ is selected from the group consisting of C₁₋₆alkyl,        C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered        heterocycloalkyl, wherein the C₁₋₆alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, hydroxy, —NO₂,        and C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl, 5- to 10-membered        heteroaryl, and 5- to 10-membered heterocycloalkyl are        optionally substituted with one or more substituents each        independently selected from the group consisting of halogen,        hydroxy, —NO₂, and C₁₋₆ alkoxy, and wherein n⁵ is 1 or 2;    -   (v)

-   -   wherein R¹¹⁰ is selected from the group consisting of H, C₁₋₆        alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, R¹¹¹ is        selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and        5- to 10-membered heteroaryl, wherein the C₁₋₆ alkyl of R¹¹⁰ or        R¹¹¹ is optionally substituted with one or more substituents        each independently selected from the group consisting of        halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl        and 5- to 10-membered heteroaryl of R¹⁰ or R¹¹ are optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆ alkoxy, and wherein n⁶ is 1 or 2;    -   (vi)

-   -   wherein R¹¹⁹ is selected from the group consisting of C₁₋₆alkyl,        C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the        C₁₋₆alkyl is optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, hydroxy, —NO₂, and C₁₋₆alkoxy, and        wherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are        optionally substituted with one or more substituents each        independently selected from the group consisting of halogen,        hydroxy, —NO₂, and C₁₋₆alkoxy, and wherein n⁸ is 1 or 2;    -   (viii)

-   -   wherein: each of R¹³⁴ and R¹³⁵ is independently selected from        the group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, 5- to        10-membered heteroaryl, —C(O)R¹³⁶, and —C(O)NR¹³⁷R¹³⁸, wherein        the C₁₋₆alkyl is optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆ alkoxy, and wherein        the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆alkoxy, and wherein n¹⁰ is 1 or 2, and wherein n¹¹ is 1 or        2;    -   R¹³⁶ is selected from the group consisting of C₁₋₆ alkyl, C₆₋₁₀        aryl, and 5- to 10-membered heteroaryl, wherein the C₁₋₆alkyl is        optionally substituted with one or more substituents each        independently selected from the group consisting of halogen,        —OH, —NO₂, and C₁₋₆ alkoxy, and wherein the C₆₋₁₀ aryl and 5- to        10-membered heteroaryl are optionally substituted with one or        more substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy; and    -   each of R¹³⁷ and R¹³⁸ is independently selected from the group        consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-membered        heteroaryl, wherein the C₁₋₆ alkyl is optionally substituted        with one or more substituents each independently selected from        the group consisting of halogen, —OH, —NO₂, and C₁₋₆ alkoxy, and        wherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are        optionally substituted with one or more substituents each        independently selected from the group consisting of halogen,        —OH, —NO₂, and C₁₋₆alkoxy;    -   (ix)

-   -   wherein each of R¹⁴⁴ and R¹⁴⁵ is independently selected from the        group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂,        C₁₋₆alkoxy, and 5- to 10-membered heterocycloalkyl, and wherein        the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂,        C₁₋₆alkoxy, and 5- to 10-membered heterocycloalkyl, and wherein        n¹² is 1 or 2; and    -   (xii)

-   -   wherein n¹⁵ is 1 or 2;        R⁵ is —NH₂ or —NHCH₃; n¹ is 4; R⁶ is —CH(CH₃)OH; R⁸ is

each of R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, and R¹⁵ is H; L is

and chiral centre *1 is in the S configuration, chiral centre *2 is inthe S configuration, chiral centre *3 is in the S configuration, chiralcentre *4 is in the R configuration, chiral centre *5 is in the Sconfiguration, chiral centre *6 is in the S configuration, chiral centre*7 is in the R configuration, and chiral centre *8 is in the Rconfiguration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula I or a salt thereof, wherein: R^(C) isNH₂; R^(N) is H; R¹ is; R³ is

R⁴ is selected from the group consisting of:

-   -   (iii)

-   -   wherein each of R⁹⁹ and R¹⁰⁰ is independently selected from the        group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein n⁴        is 1 or 2; and    -   (v)

-   -   wherein R¹¹⁰ is selected from the group consisting of H, C₁₋₆        alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, R¹¹¹ is        selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and        5- to 10-membered heteroaryl, wherein the C₁₋₆ alkyl of R¹¹⁰ or        R¹¹¹ is optionally substituted with one or more substituents        each independently selected from the group consisting of        halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl        and 5- to 10-membered heteroaryl of R¹⁰ or R¹¹ are optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆ alkoxy, and wherein n⁶ is 1 or 2;        R⁵ is —NH₂ or —NHCH₃; n¹ is 4; R⁶ is —CH(CH₃)OH; R⁸ is

each of R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, and R¹⁵ is H; L

and chiral centre *1 is in the S configuration, chiral centre *2 is inthe S configuration, chiral centre *3 is in the S configuration, chiralcentre *4 is in the R configuration, chiral centre *5 is in the Sconfiguration, chiral centre *6 is in the S configuration, chiral centre*7 is in the R configuration, and chiral centre *8 is in the Rconfiguration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula I or a salt thereof, wherein: R^(C) isNH₂; R^(N) is H; R¹ is

R⁴ is selected from the group consisting of: (iii)

wherein each of R⁹⁹ and R¹⁰⁰ is independently selected from the groupconsisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl, and wherein n⁴ is 1 or 2; and (v)

wherein R¹¹⁰ is selected from the group consisting of H, C₁₋₆alkyl,C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, and R¹¹¹ is selected fromthe group consisting of C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl, and wherein n⁶ is 1 or 2; R⁵ is —NH₂ or —NHCH₃; n¹ is 4; R⁶is —CH(CH₃)OH; R⁸ is

each of R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, and R¹⁵ is H; L is

and chiral centre *1 is in the S configuration, chiral centre *2 is inthe S configuration, chiral centre *3 is in the S configuration, chiralcentre *4 is in the R configuration, chiral centre *5 is in the Sconfiguration, chiral centre *6 is in the S configuration, chiral centre*7 is in the R configuration, and chiral centre *8 is in the Rconfiguration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula I or a salt thereof, wherein: R^(C) isNH₂; R^(N) is H; R¹ is

R⁴ is selected from the group consisting of: (iii)

wherein each of R⁹⁹ and R¹⁰⁰ is independently selected from the groupconsisting of H and C₁₋₆ alkyl, and wherein n⁴ is 1 or 2; and (v)

wherein R¹¹⁰ is H, and R¹¹ is C₆ aryl, and wherein n⁶ is 1 or 2; R⁵ is—NH₂ or —NHCH₃; n¹ is 4; R⁶ is —CH(CH₃)OH; R⁸ is

each of R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, and R¹⁵ is H; L is

and chiral centre *1 is in the S configuration, chiral centre *2 is inthe S configuration, chiral centre *3 is in the S configuration, chiralcentre *4 is in the R configuration, chiral centre *5 is in the Sconfiguration, chiral centre *6 is in the S configuration, chiral centre*7 is in the R configuration, and chiral centre *8 is in the Rconfiguration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula I or a salt thereof, wherein: R^(C) isNH₂; R^(N) is H; R¹ is; R³ is

R⁴ is: (iii)

wherein each of R⁹⁹ and R¹⁰⁰ is independently selected from the groupconsisting of H and C₁₋₆ alkyl, and wherein n⁴ is 1 or 2; R⁵ is —NH₂ or—NHCH₃; n¹ is 4; R⁶ is —CH(CH₃)OH; R⁸ is

each of R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, and R¹⁵ is H; L is

and chiral centre *1 is in the S configuration, chiral centre *2 is inthe S configuration, chiral centre *3 is in the S configuration, chiralcentre *4 is in the R configuration, chiral centre *5 is in the Sconfiguration, chiral centre *6 is in the S configuration, chiral centre*7 is in the R configuration, and chiral centre *8 is in the Rconfiguration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula I or a salt thereof, wherein: R^(C) isNH₂; R^(N) is H; R¹ is

R⁴ is: (iii)

wherein each of R⁹⁹ and R¹⁰⁰ is H, and wherein n⁴ is 1 or 2; R⁵ is —NH₂or —NHCH₃; n¹ is 4; R⁶ is —CH(CH₃)OH; R⁸ is

each of R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, and R¹⁵ is H; L is

and chiral centre *1 is in the S configuration, chiral centre *2 is inthe S configuration, chiral centre *3 is in the S configuration, chiralcentre *4 is in the R configuration, chiral centre *5 is in the Sconfiguration, chiral centre *6 is in the S configuration, chiral centre*7 is in the R configuration, and chiral centre *8 is in the Rconfiguration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula I or a salt thereof, wherein: R^(C) isNH₂; R^(N) is H; R¹ is

R⁵ is —NH₂ or —NHCH₃; n¹ is 4; R⁶ is —CH(CH₃)OH; R⁸ is

each of R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, and R¹⁵ is H; L is

and chiral centre *1 is in the S configuration, chiral centre *2 is inthe S configuration, chiral centre *3 is in the S configuration, chiralcentre *4 is in the R configuration, chiral centre *5 is in the Sconfiguration, chiral centre *6 is in the S configuration, chiral centre*7 is in the R configuration, and chiral centre *8 is in the Rconfiguration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula I or a salt thereof, wherein: R^(C) isNH₂; R^(N) is H;

R⁵ is —NH₂ or —NHCH₃; n¹ is 4; R⁶ is —CH(CH₃)OH; R⁸ is

each of R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, and R¹⁵ is H; L is

and chiral centre *1 is in the S configuration, chiral centre *2 is inthe S configuration, chiral centre *3 is in the S configuration, chiralcentre *4 is in the R configuration, chiral centre *5 is in the Sconfiguration, chiral centre *6 is in the S configuration, chiral centre*7 is in the R configuration, and chiral centre *8 is in the Rconfiguration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula II or a salt thereof, wherein: R^(C) isOH or NH₂; R^(N) is H, CH₃ or acetyl; R¹ is —C₁₋₂ alkylene(C₆₋₁₀ aryl),wherein the C₆₋₁₀ aryl is optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen and —NO₂; R³ is selected from the group consisting of —C₁₋₂alkylene(C₆ aryl) and —C₁₋₂ alkylene (6-membered heteroaryl), whereinthe C₆ aryl and the 6-membered heteroaryl are optionally substitutedwith hydroxy; R⁴ is selected from the group consisting of:

-   -   (i) —N(H)C(O)NR⁵¹R⁵² or —C₁₋₆ alkylene-N(H)C(O)NR⁵¹R⁵², wherein        each of R⁵¹ and R⁵² is independently selected from the group        consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-membered        heteroaryl, wherein the C₁₋₆alkyl is optionally substituted with        one or more substituents, and wherein the C₆₋₁₀ aryl and 5- to        10-membered heteroaryl are optionally substituted with one or        more substituents;    -   (ii) —NHC(O)R⁵⁴ or —C₁₋₆ alkylene-NHC(O)R⁵⁴, wherein R⁵⁴ is        selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and        5- to 10-membered heteroaryl, wherein the C₁₋₆ alkyl is        optionally substituted with one or more substituents, and        wherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are        optionally substituted with one or more substituents;    -   (iii) —(C₆₋₁₀ arylene)-C(O)NR⁵⁶R⁵⁷ or —C₁₋₆ alkylene-(C₆₋₁₀        arylene)-C(O)NR⁵⁶R⁵⁷, wherein each of R⁵⁶ and R⁵⁷ is        independently selected from the group consisting of H, C₁₋₆        alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the        C₁₋₆ alkyl is optionally substituted with one or more        substituents, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents;    -   (iv) —(C₆₋₁₀ arylene)-N(H)C(O)R⁵⁸ or —C₁₋₆ alkylene-(C₆₋₁₀        arylene)-N(H)C(O)R⁵⁸, wherein R⁵⁸ is selected from the group        consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, 5- to 10-membered        heteroaryl, and 5- to 10-membered heterocycloalkyl, wherein the        C₁₋₆alkyl is optionally substituted with one or more        substituents, and wherein the C₆₋₁₀ aryl, 5- to 10-membered        heteroaryl, and 5- to 10-membered heterocycloalkyl are        optionally substituted with one or more substituents;    -   (v) —(C₆₋₁₀ arylene)-N(H)C(O)NR⁶⁰R⁶¹ or —C₁₋₆ alkylene-(C₆₋₁₀        arylene)-N(H)C(O)NR⁶⁰R⁶¹, wherein each of R⁶⁰ and R⁶¹ is        independently selected from the group consisting of H, C₁₋₆        alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the        C₁₋₆alkyl is optionally substituted with one or more        substituents, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents;    -   (vi) —(C₆₋₁₀ arylene)-N(H)SO₂R⁶³ or —C₁₋₆ alkylene-(C₆₋₁₀        arylene)-N(H)SO₂R⁶³, wherein R⁶³ is selected from the group        consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-membered        heteroaryl, wherein the C₁₋₆alkyl is optionally substituted with        one or more substituents, and wherein the C₆₋₁₀ aryl and 5- to        10-membered heteroaryl are optionally substituted with one or        more substituents;    -   (vii) —(C₆₋₁₀ arylene)-SO₂NR⁶⁵R⁶⁶ or —C₁₋₆ alkylene-(C₆₋₁₀        arylene)-SO₂NR⁶⁵R⁶⁶, wherein each of R⁶⁵ and R⁶⁶ is        independently selected from the group consisting of H, C₁₋₆        alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the        C₁₋₆ alkyl is optionally substituted with one or more        substituents, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents;    -   (viii) —(C₆₋₁₀ arylene)-(C₁₋₆ alkylene)-NR⁶⁷R⁶⁸ or —C₁₋₆        alkylene-(C₆₋₁₀ arylene)-(C₁₋₆ alkylene)-NR⁶⁷R⁶⁸, wherein:        -   each of R⁶⁷ and R⁶⁸ is independently selected from the group            consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, 5- to 10-membered            heteroaryl, —C(O)R⁶⁹, and —C(O)NR⁷⁰R⁷¹, wherein the            C₁₋₆alkyl is optionally substituted with one or more            substituents, and wherein the C₆₋₁₀ aryl and 5- to            10-membered heteroaryl are optionally substituted with one            or more substituents;        -   R⁶⁹ is selected from the group consisting of C₁₋₆alkyl,            C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the            C₁₋₆alkyl is optionally substituted with one or more            substituents, and wherein the C₆₋₁₀ aryl and 5- to            10-membered heteroaryl are optionally substituted with one            or more substituents; and        -   each of R⁷⁰ and R⁷¹ is independently selected from the group            consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to            10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally            substituted with one or more substituents, and wherein the            C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally            substituted with one or more substituents;    -   (ix) —(C₆₋₁₀ arylene)-NR⁷²R⁷³ or —C₁₋₆ alkylene-(C₆₋₁₀        arylene)-NR⁷²R⁷³, wherein each of R⁷² and R⁷³ is independently        selected from the group consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl,        and 5- to 10-membered heteroaryl, wherein the C₁₋₆ alkyl is        optionally substituted with one or more substituents, and        wherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are        optionally substituted with one or more substituents;    -   (x) —(C₆₋₁₀ arylene)-OR⁷⁴ or —C₁₋₆ alkylene-(C₆₋₁₀        arylene)-OR⁷⁴, wherein R⁷⁴ is selected from the group consisting        of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5-to 10-membered heteroaryl,        wherein the C₁₋₆alkyl is optionally substituted with one or more        substituents, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents; and    -   (xi) —C₁₋₆ alkylene-(C₆₋₁₀ arylene)-N(R⁷⁵)—C(O)—CHR⁷⁶—N(H)R⁷⁸,        wherein R⁷⁵ is H or CH₃, R⁷⁶ is H or C₁₋₆alkyl optionally        substituted with one or more substituents each independently        selected from the group consisting of hydroxyl, —COOH, —NH₂,        —C(O)NH₂, and —N(H)C(O)NH₂, and R⁷⁸ is H, CH₃ or acetyl;        R⁵ is —NR⁷⁹R⁸⁰, wherein each of R⁷⁹ and R⁸⁰ is independently H        or CH₃; n¹ is 3, 4 or 5; R¹² is H or CH₃; R⁶ is C₁₋₄ alkyl        optionally substituted with hydroxy; R⁸ is —C₁₋₂ alkylene(C₆₋₁₀        aryl), wherein the C₆₋₁₀ aryl is optionally substituted with one        or more substituents each independently selected from the group        consisting of halogen, hydroxy and —NO₂; and L is

chiral centre *1 is in the S configuration; chiral centre *3 is in the Sconfiguration; chiral centre *4 is in the R configuration; chiral centre*5 is in the S configuration; chiral centre *6 is in the Sconfiguration; and chiral centre *8 is in the R configuration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula II or a salt thereof, wherein: R^(C) isOH or NH₂; R^(N) is H, CH₃ or acetyl; R¹ is —C₁₋₂ alkylene(C₆₋₁₀ aryl),wherein the C₆₋₁₀ aryl is optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen and —NO₂; R³ is selected from the group consisting of —C₁₋₂alkylene(C₆ aryl) and —C₁₋₂ alkylene(6-membered heteroaryl), wherein theC₆ aryl and the 6-membered heteroaryl are optionally substituted withhydroxy; R⁴ is selected from the group consisting of:

-   -   (i)

-   -   wherein each of R⁹⁰ and R⁹¹ is independently selected from the        group consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, wherein the C₁₋₆ alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆ alkoxy, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆ alkoxy, and wherein        n² is 3 or 4;    -   (ii)

-   -   wherein R⁹⁶ is selected from the group consisting of C₁₋₆ alkyl,        C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the        C₁₋₆alkyl is optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein        the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆ alkoxy, and wherein n³ is 3 or 4;    -   (iii)

-   -   wherein each of R⁹⁹ and R¹⁰⁰ is independently selected from the        group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein n⁴        is 1 or 2;    -   (iv)

-   -   wherein R¹⁰³ is selected from the group consisting of C₁₋₆alkyl,        C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered        heterocycloalkyl, wherein the C₁₋₆alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, hydroxy, —NO₂,        and C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl, 5- to 10-membered        heteroaryl, and 5- to 10-membered heterocycloalkyl are        optionally substituted with one or more substituents each        independently selected from the group consisting of halogen,        hydroxy, —NO₂, and C₁₋₆ alkoxy, and wherein n⁵ is 1 or 2;    -   (v)

-   -   wherein each of R¹¹⁰ and R¹¹¹ is independently selected from the        group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein n⁶        is 1 or 2;    -   (vi)

-   -   wherein R¹¹⁹ is selected from the group consisting of C₁₋₆alkyl,        C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the        C₁₋₆alkyl is optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, hydroxy, —NO₂, and C₁₋₆alkoxy, and        wherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are        optionally substituted with one or more substituents each        independently selected from the group consisting of halogen,        hydroxy, —NO₂, and C₁₋₆alkoxy, and wherein n⁸ is 1 or 2;    -   (vii)

-   -   wherein each of R¹²⁶ and R¹²⁷ is independently selected from the        group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein n⁹        is 1 or 2;    -   (viii)

-   -   wherein: each of R¹³⁴ and R¹³⁵ is independently selected from        the group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, 5- to        10-membered heteroaryl, —C(O)R¹³⁶, and —C(O)NR¹³⁷R¹³⁸, wherein        the C₁₋₆alkyl is optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆ alkoxy, and wherein        the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆alkoxy, and wherein n¹⁰ is 1 or 2, and wherein n¹¹ is 1 or        2;    -   R¹³⁶ is selected from the group consisting of C₁₋₆ alkyl, C₆₋₁₀        aryl, and 5- to 10-membered heteroaryl, wherein the C₁₋₆alkyl is        optionally substituted with one or more substituents each        independently selected from the group consisting of halogen,        —OH, —NO₂, and C₁₋₆ alkoxy, and wherein the C₆₋₁₀ aryl and 5- to        10-membered heteroaryl are optionally substituted with one or        more substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy; and    -   each of R¹³⁷ and R¹³⁸ is independently selected from the group        consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-membered        heteroaryl, wherein the C₁₋₆ alkyl is optionally substituted        with one or more substituents each independently selected from        the group consisting of halogen, —OH, —NO₂, and C₁₋₆ alkoxy, and        wherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are        optionally substituted with one or more substituents each        independently selected from the group consisting of halogen,        —OH, —NO₂, and C₁₋₆alkoxy;    -   (ix)

-   -   wherein each of R¹⁴⁴ and R¹⁴⁵ is independently selected from the        group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂,        C₁₋₆alkoxy, and 5- to 10-membered heterocycloalkyl, and wherein        the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂,        C₁₋₆alkoxy, and 5- to 10-membered heterocycloalkyl, and wherein        n¹² is 1 or 2;    -   (x)

-   -   wherein R¹⁴⁶ is selected from the group consisting of H,        C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein        the C₁₋₆alkyl is optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, C₁₋₆ alkoxy, and 5- to        10-membered heterocycloalkyl, and wherein the C₆₋₁₀ aryl and 5-        to 10-membered heteroaryl are optionally substituted with one or        more substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, C₁₋₆alkoxy, and 5- to        10-membered heterocycloalkyl, and wherein n¹³ is 1 or 2; and    -   (xi)

-   -   wherein R¹⁴⁸ is H or CH₃, R¹⁴⁹ is H or C₁₋₆ alkyl optionally        substituted with one or more substituents each independently        selected from the group consisting of hydroxyl, —COOH, —NH₂,        —C(O)NH₂, and —N(H)C(O)NH₂, and R¹⁵⁰ is H, CH₃ or acetyl, and        wherein n¹⁴ is 1 or 2;        R⁵ is —NR⁷⁹R⁸⁰, wherein each of R⁷⁹ and R⁸⁰ is independently H        or CH₃; n¹ is 3, 4 or 5; R¹² is H or CH₃; R⁶ is C₁₋₄ alkyl        optionally substituted with hydroxy; R⁸ is —C₁₋₂ alkylene(C₆₋₁₀        aryl), wherein the C₆₋₁₀ aryl is optionally substituted with one        or more substituents each independently selected from the group        consisting of halogen, hydroxy and —NO₂; and L is

chiral centre *1 is in the S configuration; chiral centre *3 is in the Sconfiguration; chiral centre *4 is in the R configuration; chiral centre*5 is in the S configuration; chiral centre *6 is in the Sconfiguration; and chiral centre *8 is in the R configuration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula II or a salt thereof, wherein: R^(C) isOH or NH₂; R^(N) is H, CH₃ or acetyl; R¹ is —C₁₋₂ alkylene(C₆₋₁₀ aryl),wherein the C₆₋₁₀ aryl is optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen and —NO₂; R³ is selected from the group consisting of —C₁₋₂alkylene(C₆ aryl) and —C₁₋₂ alkylene(6-membered heteroaryl), wherein theC₆ aryl and the 6-membered heteroaryl are optionally substituted withhydroxy; R⁴ is

wherein each of R⁹⁰ and R⁹¹ is independently selected from the groupconsisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl, wherein the C₁₋₆alkyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl and 5-to 10-membered heteroaryl are optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein n² is 3 or 4; R⁵ is—NR⁷⁹R⁸⁰, wherein each of R⁷⁹ and R⁸⁰ is independently H or CH₃; n¹ is3, 4 or 5; R¹² is H or CH₃; R⁶ is C₁₋₄ alkyl optionally substituted withhydroxy; R⁸ is —C₁₋₂ alkylene(C₆₋₁₀ aryl), wherein the C₆₋₁₀ aryl isoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, hydroxy and —NO₂; and Lis

chiral centre *1 is in the S configuration; chiral centre *3 is in the Sconfiguration; chiral centre *4 is in the R configuration; chiral centre*5 is in the S configuration; chiral centre *6 is in the Sconfiguration; and chiral centre *8 is in the R configuration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula II or a salt thereof, wherein: R^(C) isOH or NH₂; R^(N) is H, CH₃ or acetyl; R¹ is —C₁₋₂ alkylene(C₆₋₁₀ aryl),wherein the C₆₋₁₀ aryl is optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen and —NO₂; R³ is selected from the group consisting of —C₁₋₂alkylene(C₆ aryl) and —C₁₋₂ alkylene(6-membered heteroaryl), wherein theC₆ aryl and the 6-membered heteroaryl are optionally substituted withhydroxy; R⁴ is

wherein R⁹⁶ is selected from the group consisting of C₁₋₆ alkyl, C₆₋₁₀aryl, and 5- to 10-membered heteroaryl, wherein the C₁₋₆alkyl isoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, —OH, —NO₂, andC₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl and 5- to 10-membered heteroarylare optionally substituted with one or more substituents eachindependently selected from the group consisting of halogen, —OH, —NO₂,and C₁₋₆alkoxy, and wherein n³ is 3 or 4; R⁵ is —NR⁷⁹R⁸⁰, wherein eachof R⁷⁹ and R⁸⁰ is independently H or CH₃; n¹ is 3, 4 or 5; R¹² is H orCH₃; R⁶ is C₁₋₄ alkyl optionally substituted with hydroxy; R⁸ is —C₁₋₂alkylene(C₆₋₁₀ aryl), wherein the C₆₋₁₀ aryl is optionally substitutedwith one or more substituents each independently selected from the groupconsisting of halogen, hydroxy and —NO₂; and L is

chiral centre *1 is in the S configuration; chiral centre *3 is in the Sconfiguration; chiral centre *4 is in the R configuration; chiral centre*5 is in the S configuration; chiral centre *6 is in the Sconfiguration; and chiral centre *8 is in the R configuration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula II or a salt thereof, wherein: R^(C) isOH or NH₂; R^(N) is H, CH₃ or acetyl; R¹ is —C₁₋₂ alkylene(C₆₋₁₀ aryl),wherein the C₆₋₁₀ aryl is optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen and —NO₂; R³ is selected from the group consisting of —C₁₋₂alkylene(C₆ aryl) and —C₁₋₂ alkylene(6-membered heteroaryl), wherein theC₆ aryl and the 6-membered heteroaryl are optionally substituted withhydroxy; R⁴ is

wherein each of R⁹⁹ and R¹⁰⁰ is independently selected from the groupconsisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl, wherein the C₁₋₆ alkyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl and 5-to 10-membered heteroaryl are optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein n⁴ is 1 or 2; R⁵ is—NR⁷⁹R⁸⁰, wherein each of R⁷⁹ and R⁸⁰ is independently H or CH₃; n¹ is3, 4 or 5; R¹² is H or CH₃; R⁶ is C₁₋₄ alkyl optionally substituted withhydroxy; R⁸ is —C₁₋₂ alkylene(C₆₋₁₀ aryl), wherein the C₆₋₁₀ aryl isoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, hydroxy and —NO₂; and Lis

chiral centre *1 is in the S configuration; chiral centre *3 is in the Sconfiguration; chiral centre *4 is in the R configuration; chiral centre*5 is in the S configuration; chiral centre *6 is in the Sconfiguration; and chiral centre *8 is in the R configuration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula II or a salt thereof, wherein: R^(C) isOH or NH₂; R^(N) is H, CH₃ or acetyl; R¹ is —C₁₋₂ alkylene(C₆₋₁₀ aryl),wherein the C₆₋₁₀ aryl is optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen and —NO₂; R³ is selected from the group consisting of —C₁₋₂alkylene(C₆ aryl) and —C₁₋₂ alkylene(6-membered heteroaryl), wherein theC₆ aryl and the 6-membered heteroaryl are optionally substituted withhydroxy; R⁴ is

wherein R¹⁰³ is selected from the group consisting of C₁₋₆ alkyl, C₆₋₁₀aryl, 5-to 10-membered heteroaryl, and 5- to 10-memberedheterocycloalkyl, wherein the C₁₋₆alkyl is optionally substituted withone or more substituents each independently selected from the groupconsisting of halogen, hydroxy, —NO₂, and C₁₋₆ alkoxy, and wherein theC₆₋₁₀ aryl, 5- to 10-membered heteroaryl, and 5- to 10-memberedheterocycloalkyl are optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen, hydroxy, —NO₂, and C₁₋₆alkoxy, and wherein n⁵ is 1 or 2; R⁵ is—NR⁷⁹R⁸⁰, wherein each of R⁷⁹ and R⁸⁰ is independently H or CH₃; n¹ is3, 4 or 5; R¹² is H or CH₃; R⁶ is C₁₋₄ alkyl optionally substituted withhydroxy; R⁸ is —C₁₋₂ alkylene(C₆₋₁₀ aryl), wherein the C₆₋₁₀ aryl isoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, hydroxy and —NO₂; and Lis

chiral centre *1 is in the S configuration; chiral centre *3 is in the Sconfiguration; chiral centre *4 is in the R configuration; chiral centre*5 is in the S configuration; chiral centre *6 is in the Sconfiguration; and chiral centre *8 is in the R configuration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula II or a salt thereof, wherein: R^(C) isOH or NH₂; R^(N) is H, CH₃ or acetyl; R¹ is —C₁₋₂ alkylene(C₆₋₁₀ aryl),wherein the C₆₋₁₀ aryl is optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen and —NO₂; R³ is selected from the group consisting of —C₁₋₂alkylene(C₆ aryl) and —C₁₋₂ alkylene(6-membered heteroaryl), wherein theC₆ aryl and the 6-membered heteroaryl are optionally substituted withhydroxy; R⁴ is

wherein each of R¹¹⁰ and R¹¹¹ is independently selected from the groupconsisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl, wherein the C₁₋₆ alkyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl and 5-to 10-membered heteroaryl are optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein n⁶ is 1 or 2; R⁵ is—NR⁷⁹R⁸⁰, wherein each of R⁷⁹ and R⁸⁰ is independently H or CH₃; n¹ is3, 4 or 5; R¹² is H or CH₃; R⁶ is C₁₋₄ alkyl optionally substituted withhydroxy; R⁸ is —C₁₋₂ alkylene(C₆₋₁₀ aryl), wherein the C₆₋₁₀ aryl isoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, hydroxy and —NO₂; and Lis

chiral centre *1 is in the S configuration; chiral centre *3 is in the Sconfiguration; chiral centre *4 is in the R configuration; chiral centre*5 is in the S configuration; chiral centre *6 is in the Sconfiguration; and chiral centre *8 is in the R configuration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula II or a salt thereof, wherein: R^(C) isOH or NH₂; R^(N) is H, CH₃ or acetyl; R¹ is —C₁₋₂ alkylene(C₆₋₁₀ aryl),wherein the C₆₋₁₀ aryl is optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen and —NO₂; R³ is selected from the group consisting of —C₁₋₂alkylene(C₆ aryl) and —C₁₋₂ alkylene(6-membered heteroaryl), wherein theC₆ aryl and the 6-membered heteroaryl are optionally substituted withhydroxy; R⁴ is

wherein R¹¹⁹ is selected from the group consisting of C₁₋₆ alkyl, C₆₋₁₀aryl, and 5- to 10-membered heteroaryl, wherein the C₁₋₆alkyl isoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, hydroxy, —NO₂, andC₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl and 5- to 10-membered heteroarylare optionally substituted with one or more substituents eachindependently selected from the group consisting of halogen, hydroxy,—NO₂, and C₁₋₆alkoxy, and wherein n⁸ is 1 or 2; R⁵ is —NR⁷⁹R⁸⁰, whereineach of R⁷⁹ and R⁸⁰ is independently H or CH₃; n¹ is 3, 4 or 5; R¹² is Hor CH₃; R⁶ is C₁₋₄ alkyl optionally substituted with hydroxy; R⁸ is—C₁₋₂ alkylene(C₆₋₁₀ aryl), wherein the C₆₋₁₀ aryl is optionallysubstituted with one or more substituents each independently selectedfrom the group consisting of halogen, hydroxy and —NO₂; and L is

chiral centre *1 is in the S configuration; chiral centre *3 is in the Sconfiguration; chiral centre *4 is in the R configuration; chiral centre*5 is in the S configuration; chiral centre *6 is in the Sconfiguration; and chiral centre *8 is in the R configuration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula II or a salt thereof, wherein: R^(C) isOH or NH₂; R^(N) is H, CH₃ or acetyl; R¹ is —C₁₋₂ alkylene(C₆₋₁₀ aryl),wherein the C₆₋₁₀ aryl is optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen and —NO₂; R³ is selected from the group consisting of —C₁₋₂alkylene(C₆ aryl) and —C₁₋₂ alkylene(6-membered heteroaryl), wherein theC₆ aryl and the 6-membered heteroaryl are optionally substituted withhydroxy; R⁴ is

wherein each of R¹²⁶ and R¹²⁷ is independently selected from the groupconsisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl, wherein the C₁₋₆ alkyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl and 5-to 10-membered heteroaryl are optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein n⁹ is 1 or 2; R⁵ is—NR⁷⁹R⁸⁰, wherein each of R⁷⁹ and R⁸⁰ is independently H or CH₃; n¹ is3, 4 or 5; R¹² is H or CH₃; R⁶ is C₁₋₄ alkyl optionally substituted withhydroxy; R⁸ is —C₁₋₂ alkylene(C₆₋₁₀ aryl), wherein the C₆₋₁₀ aryl isoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, hydroxy and —NO₂; and Lis

chiral centre *1 is in the S configuration; chiral centre *3 is in the Sconfiguration; chiral centre *4 is in the R configuration; chiral centre*5 is in the S configuration; chiral centre *6 is in the Sconfiguration; and chiral centre *8 is in the R configuration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula II or a salt thereof, wherein: R^(C) isOH or NH₂; R^(N) is H, CH₃ or acetyl; R¹ is —C₁₋₂ alkylene(C₆₋₁₀ aryl),wherein the C₆₋₁₀ aryl is optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen and —NO₂; R³ is selected from the group consisting of —C₁₋₂alkylene(C₆ aryl) and —C₁₋₂ alkylene(6-membered heteroaryl), wherein theC₆ aryl and the 6-membered heteroaryl are optionally substituted withhydroxy;

R⁴ is

wherein:each of R¹³⁴ and R¹³⁵ is independently selected from the groupconsisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, 5-to 10-membered heteroaryl,—C(O)R¹³⁶, and —C(O)NR¹³⁷R¹³⁸, wherein the C₁₋₆alkyl is optionallysubstituted with one or more substituents each independently selectedfrom the group consisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy, andwherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionallysubstituted with one or more substituents each independently selectedfrom the group consisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy, andwherein n¹⁰ is 1 or 2, and wherein n¹¹ is 1 or 2;R¹³⁶ is selected from the group consisting of C₁₋₆ alkyl, C₆₋₁₀ aryl,and 5- to 10-membered heteroaryl, wherein the C₁₋₆alkyl is optionallysubstituted with one or more substituents each independently selectedfrom the group consisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy, andwherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionallysubstituted with one or more substituents each independently selectedfrom the group consisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy; andeach of R¹³⁷ and R¹³⁸ is independently selected from the groupconsisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl, wherein the C₁₋₆alkyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen, —OH, —NO₂, and C₁₋₆ alkoxy, and wherein the C₆₋₁₀ aryl and5- to 10-membered heteroaryl are optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen, —OH, —NO₂, and C₁₋₆ alkoxy;R⁵ is —NR⁷⁹R⁸⁰, wherein each of R⁷⁹ and R⁸⁰ is independently H or CH₃;n¹ is 3, 4 or 5; R¹² is H or CH₃; R⁶ is C₁₋₄ alkyl optionallysubstituted with hydroxy; R⁸ is —C₁₋₂ alkylene(C₆₋₁₀ aryl), wherein theC₆₋₁₀ aryl is optionally substituted with one or more substituents eachindependently selected from the group consisting of halogen, hydroxy and—NO₂; and L is

chiral centre *1 is in the S configuration; chiral centre *3 is in the Sconfiguration; chiral centre *4 is in the R configuration; chiral centre*5 is in the S configuration; chiral centre *6 is in the Sconfiguration; and chiral centre *8 is in the R configuration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula II or a salt thereof, wherein: R^(C) isOH or NH₂; R^(N) is H, CH₃ or acetyl; R¹ is —C₁₋₂ alkylene(C₆₋₁₀ aryl),wherein the C₆₋₁₀ aryl is optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen and —NO₂; R³ is selected from the group consisting of —C₁₋₂alkylene(C₆ aryl) and —C₁₋₂ alkylene(6-membered heteroaryl), wherein theC₆ aryl and the 6-membered heteroaryl are optionally substituted withhydroxy; R⁴ is

wherein each of R¹⁴⁴ and R¹⁴⁵ is independently selected from the groupconsisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl, wherein the C₁₋₆ alkyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen, —OH, —NO₂, C₁₋₆alkoxy, and 5- to 10-memberedheterocycloalkyl, and wherein the C₆₋₁₀ aryl and 5- to 10-memberedheteroaryl are optionally substituted with one or more substituents eachindependently selected from the group consisting of halogen, —OH, —NO₂,C₁₋₆ alkoxy, and 5- to 10-membered heterocycloalkyl, and wherein n¹² is1 or 2; R⁶ is —NR⁷⁹R⁸⁰, wherein each of R⁷⁹ and R⁸⁰ is independently Hor CH₃; n¹ is 3, 4 or 5; R¹² is H or CH₃; R⁶ is C₁₋₄ alkyl optionallysubstituted with hydroxy; R⁸ is —C₁₋₂ alkylene(C₆₋₁₀ aryl), wherein theC₆₋₁₀ aryl is optionally substituted with one or more substituents eachindependently selected from the group consisting of halogen, hydroxy and—NO₂; and L is

chiral centre *1 is in the S configuration; chiral centre *3 is in the Sconfiguration; chiral centre *4 is in the R configuration; chiral centre*5 is in the S configuration; chiral centre *6 is in the Sconfiguration; and chiral centre *8 is in the R configuration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula II or a salt thereof, wherein: R^(C) isOH or NH₂; R^(N) is H, CH₃ or acetyl; R¹ is —C₁₋₂ alkylene(C₆₋₁₀ aryl),wherein the C₆₋₁₀ aryl is optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen and —NO₂; R³ is selected from the group consisting of —C₁₋₂alkylene(C₆ aryl) and —C₁₋₂ alkylene(6-membered heteroaryl), wherein theC₆ aryl and the 6-membered heteroaryl are optionally substituted withhydroxy; R⁴ is

wherein R¹⁴⁶ is selected from the group consisting of H, C₁₋₆ alkyl,C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the C₁₋₆ alkyl isoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, —OH, —NO₂, C₁₋₆ alkoxy,and 5- to 10-membered heterocycloalkyl, and wherein the C₆₋₁₀ aryl and5- to 10-membered heteroaryl are optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen, —OH, —NO₂, C₁₋₆ alkoxy, and 5- to 10-membered heterocycloalkyl,and wherein n¹³ is 1 or 2; R⁵ is —NR⁷⁹R⁸⁰, wherein each of R⁷⁹ and R⁸⁰is independently H or CH₃; n¹ is 3, 4 or 5; R¹² is H or CH₃; R⁶ is C₁₋₄alkyl optionally substituted with hydroxy; R⁸ is —C₁₋₂ alkylene(C₆₋₁₀aryl), wherein the C₆₋₁₀ aryl is optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen, hydroxy and —NO₂; and L is

chiral centre *1 is in the S configuration; chiral centre *3 is in the Sconfiguration; chiral centre *4 is in the R configuration; chiral centre*5 is in the S configuration; chiral centre *6 is in the Sconfiguration; and chiral centre *8 is in the R configuration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula II or a salt thereof, wherein: R^(C) isOH or NH₂; R^(N) is H, CH₃ or acetyl; R¹ is —C₁₋₂ alkylene(C₆₋₁₀ aryl),wherein the C₆₋₁₀ aryl is optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen and —NO₂; R³ is selected from the group consisting of —C₁₋₂alkylene(C₆ aryl) and —C₁₋₂ alkylene(6-membered heteroaryl), wherein theC₆ aryl and the 6-membered heteroaryl are optionally substituted withhydroxy; R⁴ is

wherein R¹⁴⁸ is H or CH₃, R¹⁴⁹ is H or C₁₋₆alkyl optionally substitutedwith one or more substituents each independently selected from the groupconsisting of hydroxyl, —COOH, —NH₂, —C(O)NH₂, and —N(H)C(O)NH₂, andR¹⁵⁰ is H, CH₃ or acetyl, and wherein n¹⁴ is 1 or 2; R⁵ is —NR⁷⁹R⁸⁰,wherein each of R⁷⁹ and R⁸⁰ is independently H or CH₃; n¹ is 3, 4 or 5;R¹² is H or CH₃; R⁶ is C₁₋₄ alkyl optionally substituted with hydroxy;R⁸ is —C₁₋₂ alkylene(C₆₋₁₀ aryl), wherein the C₆₋₁₀ aryl is optionallysubstituted with one or more substituents each independently selectedfrom the group consisting of halogen, hydroxy and —NO₂; and L is

chiral centre *1 is in the S configuration; chiral centre *3 is in the Sconfiguration; chiral centre *4 is in the R configuration; chiral centre*5 is in the S configuration; chiral centre *6 is in the Sconfiguration; and chiral centre *8 is in the R configuration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula II or a salt thereof, wherein: R^(C) isOH or NH₂; R^(N) is H, CH₃ or acetyl; R¹ is —CH₂-phenyl or—CH₂-naphthyl, wherein the phenyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen and —NO₂; R³ is —CH₂-phenyl or —CH₂-pyridinyl, wherein thephenyl is optionally substituted with hydroxyl; R⁴ is selected from thegroup consisting of:

-   -   (i)

-   -   wherein each of R⁹⁰ and R⁹¹ is independently selected from the        group consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, wherein the C₁₋₆ alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆ alkoxy, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆ alkoxy, and wherein        n² is 3 or 4;    -   (ii)

-   -   wherein R⁹⁶ is selected from the group consisting of C₁₋₆ alkyl,        C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the        C₁₋₆alkyl is optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein        the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆ alkoxy, and wherein n³ is 3 or 4;    -   (iii)

-   -   wherein each of R⁹⁹ and R¹⁰⁰ is independently selected from the        group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein n⁴        is 1 or 2;    -   (iv)

-   -   wherein R¹⁰³ is selected from the group consisting of C₁₋₆alkyl,        C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered        heterocycloalkyl, wherein the C₁₋₆alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, hydroxy, —NO₂,        and C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl, 5- to 10-membered        heteroaryl, and 5- to 10-membered heterocycloalkyl are        optionally substituted with one or more substituents each        independently selected from the group consisting of halogen,        hydroxy, —NO₂, and C₁₋₆ alkoxy, and wherein n⁵ is 1 or 2;    -   (v)

-   -   wherein each of R¹¹⁰ and R¹¹¹ is independently selected from the        group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein n⁶        is 1 or 2;    -   (vi)

-   -   wherein R¹¹⁹ is selected from the group consisting of C₁₋₆alkyl,        C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the        C₁₋₆alkyl is optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, hydroxy, —NO₂, and C₁₋₆alkoxy, and        wherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are        optionally substituted with one or more substituents each        independently selected from the group consisting of halogen,        hydroxy, —NO₂, and C₁₋₆alkoxy, and wherein n⁸ is 1 or 2;    -   (vii)

-   -   wherein each of R¹²⁶ and R¹²⁷ is independently selected from the        group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl and 5- to 10-membered        heteroaryl are optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein n⁹        is 1 or 2;    -   (viii)

-   -   wherein: each of R¹³⁴ and R¹³⁵ is independently selected from        the group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, 5- to        10-membered heteroaryl, —C(O)R¹³⁶, and —C(O)NR¹³⁷R¹³⁸, wherein        the C₁₋₆alkyl is optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆ alkoxy, and wherein        the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂, and        C₁₋₆alkoxy, and wherein n¹⁰ is 1 or 2, and wherein n¹¹ is 1 or        2;    -   R¹³⁶ is selected from the group consisting of C₁₋₆ alkyl, C₆₋₁₀        aryl, and 5- to 10-membered heteroaryl, wherein the C₁₋₆alkyl is        optionally substituted with one or more substituents each        independently selected from the group consisting of halogen,        —OH, —NO₂, and C₁₋₆ alkoxy, and wherein the C₆₋₁₀ aryl and 5- to        10-membered heteroaryl are optionally substituted with one or        more substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy; and    -   each of R¹³⁷ and R¹³⁸ is independently selected from the group        consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-membered        heteroaryl, wherein the C₁₋₆ alkyl is optionally substituted        with one or more substituents each independently selected from        the group consisting of halogen, —OH, —NO₂, and C₁₋₆ alkoxy, and        wherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are        optionally substituted with one or more substituents each        independently selected from the group consisting of halogen,        —OH, —NO₂, and C₁₋₆alkoxy;    -   (ix)

-   -   wherein each of R¹⁴⁴ and R¹⁴⁵ is independently selected from the        group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to        10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂,        C₁₋₆alkoxy, and 5- to 10-membered heterocycloalkyl, and wherein        the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally        substituted with one or more substituents each independently        selected from the group consisting of halogen, —OH, —NO₂,        C₁₋₆alkoxy, and 5- to 10-membered heterocycloalkyl, and wherein        n¹² is 1 or 2;    -   (x)

-   -   wherein R¹⁴⁶ is selected from the group consisting of H,        C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein        the C₁₋₆alkyl is optionally substituted with one or more        substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, C₁₋₆ alkoxy, and 5- to        10-membered heterocycloalkyl, and wherein the C₆₋₁₀ aryl and 5-        to 10-membered heteroaryl are optionally substituted with one or        more substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, C₁₋₆alkoxy, and 5- to        10-membered heterocycloalkyl, and wherein n¹³ is 1 or 2; and    -   (xi)

-   -   wherein R¹⁴⁸ is H or CH₃, R¹⁴⁹ is H or C₁₋₆ alkyl optionally        substituted with one or more substituents each independently        selected from the group consisting of hydroxyl, —COOH, —NH₂,        —C(O)NH₂, and —N(H)C(O)NH₂, and R¹⁵⁰ is H, CH₃ or acetyl, and        wherein n¹⁴ is 1 or 2;        R⁵ is —NR⁷⁹R⁸⁰, wherein each of R⁷⁹ and R⁸⁰ is independently H        or CH₃; n¹ is 3, 4 or 5; R¹² is H or CH₃; R⁶ is C₁₋₄ alkyl        optionally substituted with hydroxy; R⁸ is —CH₂-phenyl or        —CH₂-naphthyl, wherein the phenyl is optionally substituted with        one or more substituents each independently selected from the        group consisting of halogen, hydroxyl, and —NO₂; and L is

chiral centre *1 is in the S configuration; chiral centre *3 is in the Sconfiguration; chiral centre *4 is in the R configuration; chiral centre*5 is in the S configuration; chiral centre *6 is in the Sconfiguration; and chiral centre *8 is in the R configuration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula II or a salt thereof, wherein: R^(C) isOH or NH₂; R^(N) is H, CH₃ or acetyl; R¹ is —CH₂-phenyl or—CH₂-naphthyl, wherein the phenyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen and —NO₂; R³ is —CH₂-phenyl or —CH₂-pyridinyl, wherein thephenyl is optionally substituted with hydroxyl; R⁴ is

wherein each of R⁹⁰ and R⁹¹ is independently selected from the groupconsisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl, wherein the C₁₋₆ alkyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl and 5-to 10-membered heteroaryl are optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein n² is 3 or 4; R⁵ is—NR⁷⁹R⁸⁰, wherein each of R⁷⁹ and R⁸⁰ is independently H or CH₃; n¹ is3, 4 or 5; R¹² is H or CH₃; R⁶ is C₁₋₄ alkyl optionally substituted withhydroxy; R⁸ is —CH₂-phenyl or —CH₂-naphthyl, wherein the phenyl isoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, hydroxyl, and —NO₂; and Lis

chiral centre *1 is in the S configuration; chiral centre *3 is in the Sconfiguration; chiral centre *4 is in the R configuration; chiral centre*5 is in the S configuration; chiral centre *6 is in the Sconfiguration; and chiral centre *8 is in the R configuration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula II or a salt thereof, wherein: R^(C) isOH or NH₂; R^(N) is H, CH₃ or acetyl; R¹ is —CH₂-phenyl or—CH₂-naphthyl, wherein the phenyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen and —NO₂; R³ is —CH₂-phenyl or —CH₂-pyridinyl, wherein thephenyl is optionally substituted with hydroxyl; R⁴ is

wherein each of R⁹⁰ and R⁹¹ is H, and wherein n² is 3 or 4; R⁵ is—NR⁷⁹R⁸⁰, wherein each of R⁷⁹ and R⁸⁰ is independently H or CH₃; n¹ is3, 4 or 5; R¹² is H or CH₃; R⁶ is C₁₋₄ alkyl optionally substituted withhydroxy; R⁸ is —CH₂-phenyl or —CH₂-naphthyl, wherein the phenyl isoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, hydroxyl, and —NO₂; and Lis

chiral centre *1 is in the S configuration; chiral centre *3 is in the Sconfiguration; chiral centre *4 is in the R configuration; chiral centre*5 is in the S configuration; chiral centre *6 is in the Sconfiguration; and chiral centre *8 is in the R configuration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula II or a salt thereof, wherein: R^(C) isOH or NH₂; R^(N) is H, CH₃ or acetyl; R¹ is —CH₂-phenyl or—CH₂-naphthyl, wherein the phenyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen and —NO₂; R³ is —CH₂-phenyl or —CH₂-pyridinyl, wherein thephenyl is optionally substituted with hydroxyl; R⁴ is

wherein R⁹⁶ is selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀aryl, and 5- to 10-membered heteroaryl, wherein the C₁₋₆alkyl isoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, —OH, —NO₂, andC₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl and 5- to 10-membered heteroarylare optionally substituted with one or more substituents eachindependently selected from the group consisting of halogen, —OH, —NO₂,and C₁₋₆alkoxy, and wherein n³ is 3 or 4; R⁵ is —NR⁷⁹R⁸⁰, wherein eachof R⁷⁹ and R⁸⁰ is independently H or CH₃; n¹ is 3, 4 or 5; R¹² is H orCH₃; R⁶ is C₁₋₄ alkyl optionally substituted with hydroxy; R⁸ is—CH₂-phenyl or —CH₂— naphthyl, wherein the phenyl is optionallysubstituted with one or more substituents each independently selectedfrom the group consisting of halogen, hydroxyl, and —NO₂; and L is

chiral centre *1 is in the S configuration; chiral centre *3 is in the Sconfiguration; chiral centre *4 is in the R configuration; chiral centre*5 is in the S configuration; chiral centre *6 is in the Sconfiguration; and chiral centre *8 is in the R configuration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula II or a salt thereof, wherein: R^(C) isOH or NH₂; R^(N) is H, CH₃ or acetyl; R¹ is —CH₂-phenyl or—CH₂-naphthyl, wherein the phenyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen and —NO₂; R³ is —CH₂-phenyl or —CH₂-pyridinyl, wherein thephenyl is optionally substituted with hydroxyl; R⁴ is

wherein R⁹⁶ is 5- to 10-membered heteroaryl optionally substituted withone or more substituents each independently selected from the groupconsisting of halogen, hydroxy, —NO₂, and C₁₋₆ alkoxy, and n³ is 1; R⁵is —NR⁷⁹R⁸⁰, wherein each of R⁷⁹ and R⁸⁰ is independently H or CH₃; n¹is 3, 4 or 5; R¹² is H or CH₃; R⁶ is C₁₋₄ alkyl optionally substitutedwith hydroxy; R⁸ is —CH₂-phenyl or —CH₂-naphthyl, wherein the phenyl isoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, hydroxyl, and —NO₂; and Lis

chiral centre *1 is in the S configuration; chiral centre *3 is in the Sconfiguration; chiral centre *4 is in the R configuration; chiral centre*5 is in the S configuration; chiral centre *6 is in the Sconfiguration; and chiral centre *8 is in the R configuration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula II or a salt thereof, wherein: R^(C) isOH or NH₂; R^(N) is H, CH₃ or acetyl; R¹ is —CH₂-phenyl or—CH₂-naphthyl, wherein the phenyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen and —NO₂; R³ is —CH₂-phenyl or —CH₂-pyridinyl, wherein thephenyl is optionally substituted with hydroxyl; R⁴ is

wherein R⁹⁶ is pyridinyl optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen, hydroxy, —NO₂, and C₁₋₆ alkoxy, and n³ is 1; R⁵ is —NR⁷⁹R⁸⁰,wherein each of R⁷⁹ and R⁸⁰ is independently H or CH₃; n¹ is 3, 4 or 5;R¹² is H or CH₃; R⁶ is C₁₋₄ alkyl optionally substituted with hydroxy;R⁸ is —CH₂-phenyl or —CH₂-naphthyl, wherein the phenyl is optionallysubstituted with one or more substituents each independently selectedfrom the group consisting of halogen, hydroxyl, and —NO₂; and L is

chiral centre *1 is in the S configuration; chiral centre *3 is in the Sconfiguration; chiral centre *4 is in the R configuration; chiral centre*5 is in the S configuration; chiral centre *6 is in the Sconfiguration; and chiral centre *8 is in the R configuration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula II or a salt thereof, wherein: R^(C) isOH or NH₂; R^(N) is H, CH₃ or acetyl; R¹ is —CH₂-phenyl or—CH₂-naphthyl, wherein the phenyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen and —NO₂; R³ is —CH₂-phenyl or —CH₂-pyridinyl, wherein thephenyl is optionally substituted with hydroxyl; R⁴ is

wherein each of R⁹⁹ and R¹⁰⁰ is independently selected from the groupconsisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl, wherein the C₁₋₆alkyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen, —OH, —NO₂, and C₁₋₆ alkoxy, and wherein the C₆₋₁₀ aryl and5- to 10-membered heteroaryl are optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein n⁴ is 1 or 2; R⁵ is—NR⁷⁹R⁸⁰, wherein each of R⁷⁹ and R⁸⁰ is independently H or CH₃; n¹ is3, 4 or 5; R¹² is H or CH₃; R⁶ is C₁₋₄ alkyl optionally substituted withhydroxy; R⁸ is —CH₂-phenyl or —CH₂-naphthyl, wherein the phenyl isoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, hydroxyl, and —NO₂; and Lis

chiral centre *1 is in the S configuration; chiral centre *3 is in the Sconfiguration; chiral centre *4 is in the R configuration; chiral centre*5 is in the S configuration; chiral centre *6 is in the Sconfiguration; and chiral centre *8 is in the R configuration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula II or a salt thereof, wherein: R^(C) isOH or NH₂; R^(N) is H, CH₃ or acetyl; R¹ is —CH₂-phenyl or—CH₂-naphthyl, wherein the phenyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen and —NO₂; R³ is —CH₂-phenyl or —CH₂-pyridinyl, wherein thephenyl is optionally substituted with hydroxyl; R⁴ is

wherein each of R⁹⁹ and R¹⁰⁰ is H, and n⁴ is 1; R⁵ is —NR⁷⁹R⁸⁰, whereineach of R⁷⁹ and R⁸⁰ is independently H or CH₃; n¹ is 3, 4 or 5; R¹² is Hor CH₃; R⁶ is C₁₋₄ alkyl optionally substituted with hydroxy; R⁸ is—CH₂-phenyl or —CH₂-naphthyl, wherein the phenyl is optionallysubstituted with one or more substituents each independently selectedfrom the group consisting of halogen, hydroxyl, and —NO₂; and L is

chiral centre *1 is in the S configuration; chiral centre *3 is in the Sconfiguration; chiral centre *4 is in the R configuration; chiral centre*5 is in the S configuration; chiral centre *6 is in the Sconfiguration; and chiral centre *8 is in the R configuration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula II or a salt thereof, wherein: R^(C) isOH or NH₂; R^(N) is H, CH₃ or acetyl; R¹ is —CH₂-phenyl or—CH₂-naphthyl, wherein the phenyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen and —NO₂; R³ is —CH₂-phenyl or —CH₂-pyridinyl, wherein thephenyl is optionally substituted with hydroxyl; R⁴ is

wherein R¹⁰³ is selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀aryl, 5- to 10-membered heteroaryl, and 5- to 10-memberedheterocycloalkyl, wherein the C₁₋₆alkyl is optionally substituted withone or more substituents each independently selected from the groupconsisting of halogen, hydroxy, —NO₂, and C₁₋₆alkoxy, and wherein theC₆₋₁₀ aryl, 5- to 10-membered heteroaryl, and 5- to 10-memberedheterocycloalkyl are optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen, hydroxy, —NO₂, and C₁₋₆ alkoxy, and wherein n⁵ is 1 or 2; R⁵ is—NR⁷⁹R⁸⁰, wherein each of R⁷⁹ and R⁸⁰ is independently H or CH₃; n¹ is3, 4 or 5; R¹² is H or CH₃; R⁶ is C₁₋₄ alkyl optionally substituted withhydroxy; R⁸ is —CH₂-phenyl or —CH₂-naphthyl, wherein the phenyl isoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, hydroxyl, and —NO₂; and Lis

chiral centre *1 is in the S configuration; chiral centre *3 is in the Sconfiguration; chiral centre *4 is in the R configuration; chiral centre*5 is in the S configuration; chiral centre *6 is in the Sconfiguration; and chiral centre *8 is in the R configuration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula II or a salt thereof, wherein: R^(C) isOH or NH₂; R^(N) is H, CH₃ or acetyl; R¹ is —CH₂-phenyl or—CH₂-naphthyl, wherein the phenyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen and —NO₂; R³ is —CH₂-phenyl or —CH₂-pyridinyl, wherein thephenyl is optionally substituted with hydroxyl; R⁴ is

wherein R¹⁰³ is pyrrolidinyl and n⁵ is 1; R⁵ is —NR⁷⁹R⁸⁰, wherein eachof R⁷⁹ and R⁸⁰ is independently H or CH₃; n¹ is 3, 4 or 5; R¹² is H orCH₃; R⁶ is C₁₋₄ alkyl optionally substituted with hydroxy; R⁸ is—CH₂-phenyl or —CH₂-naphthyl, wherein the phenyl is optionallysubstituted with one or more substituents each independently selectedfrom the group consisting of halogen, hydroxyl, and —NO₂; and L is

chiral centre *1 is in the S configuration; chiral centre *3 is in the Sconfiguration; chiral centre *4 is in the R configuration; chiral centre*5 is in the S configuration; chiral centre *6 is in the Sconfiguration; and chiral centre *8 is in the R configuration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula II or a salt thereof, wherein: R^(C) isOH or NH₂; R^(N) is H, CH₃ or acetyl; R¹ is —CH₂-phenyl or—CH₂-naphthyl, wherein the phenyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen and —NO₂; R³ is —CH₂-phenyl or —CH₂-pyridinyl, wherein thephenyl is optionally substituted with hydroxyl; R⁴ is

wherein each of R¹¹⁰ and R¹¹¹ is independently selected from the groupconsisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl, wherein the C₁₋₆alkyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen, —OH, —NO₂, and C₁₋₆ alkoxy, and wherein the C₆₋₁₀ aryl and5- to 10-membered heteroaryl are optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein n⁶ is 1 or 2; R⁵ is—NR⁷⁹R⁸⁰, wherein each of R⁷⁹ and R⁸⁰ is independently H or CH₃; n¹ is3, 4 or 5; R¹² is H or CH₃; R⁶ is C₁₋₄ alkyl optionally substituted withhydroxy; R⁸ is —CH₂-phenyl or —CH₂-naphthyl, wherein the phenyl isoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, hydroxyl, and —NO₂; and Lis

chiral centre *1 is in the S configuration; chiral centre *3 is in the Sconfiguration; chiral centre *4 is in the R configuration; chiral centre*5 is in the S configuration; chiral centre *6 is in the Sconfiguration; and chiral centre *8 is in the R configuration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula II or a salt thereof, wherein: R^(C) isOH or NH₂; R^(N) is H, CH₃ or acetyl; R¹ is —CH₂-phenyl or—CH₂-naphthyl, wherein the phenyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen and —NO₂; R³ is —CH₂-phenyl or —CH₂-pyridinyl, wherein thephenyl is optionally substituted with hydroxyl; R⁴ is

wherein R¹¹⁰ is H and R¹¹ is phenyl, and n⁶ is 1; R⁵ is —NR⁷⁹R⁸⁰,wherein each of R⁷⁹ and R⁸⁰ is independently H or CH₃; n¹ is 3, 4 or 5;R¹² is H or CH₃; R⁶ is C₁₋₄ alkyl optionally substituted with hydroxy;R⁸ is —CH₂-phenyl or —CH₂-naphthyl, wherein the phenyl is optionallysubstituted with one or more substituents each independently selectedfrom the group consisting of halogen, hydroxyl, and —NO₂; and L is

chiral centre *1 is in the S configuration; chiral centre *3 is in the Sconfiguration; chiral centre *4 is in the R configuration; chiral centre*5 is in the S configuration; chiral centre *6 is in the Sconfiguration; and chiral centre *8 is in the R configuration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula II or a salt thereof, wherein: R^(C) isOH or NH₂; R^(N) is H, CH₃ or acetyl; R¹ is —CH₂-phenyl or—CH₂-naphthyl, wherein the phenyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen and —NO₂; R³ is —CH₂-phenyl or —CH₂-pyridinyl, wherein thephenyl is optionally substituted with hydroxyl; R⁴ is

wherein R¹¹⁹ is selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀aryl, and 5- to 10-membered heteroaryl, wherein the C₁₋₆alkyl isoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, hydroxy, —NO₂, and C₁₋₆alkoxy, and wherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl areoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, hydroxy, —NO₂, and C₁₋₆alkoxy, and wherein n⁸ is 1 or 2; R⁵ is —NR⁷⁹R⁸⁰, wherein each of R⁷⁹and R⁸⁰ is independently H or CH₃; n¹ is 3, 4 or 5; R¹² is H or CH₃; R⁶is C₁₋₄ alkyl optionally substituted with hydroxy; R⁸ is —CH₂-phenyl or—CH₂-naphthyl, wherein the phenyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen, hydroxyl, and —NO₂; and L is

chiral centre *1 is in the S configuration; chiral centre *3 is in the Sconfiguration; chiral centre *4 is in the R configuration; chiral centre*5 is in the S configuration; chiral centre *6 is in the Sconfiguration; and chiral centre *8 is in the R configuration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula II or a salt thereof, wherein: R^(C) isOH or NH₂; R^(N) is H, CH₃ or acetyl; R¹ is —CH₂-phenyl or—CH₂-naphthyl, wherein the phenyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen and —NO₂; R³ is —CH₂-phenyl or —CH₂-pyridinyl, wherein thephenyl is optionally substituted with hydroxyl; R⁴ is

wherein R¹¹⁹ is C₆ aryl optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen, hydroxy, —NO₂, and C₁₋₆alkoxy, and n⁸ is 1; R⁶ is —NR⁷⁹R⁸⁰,wherein each of R⁷⁹ and R⁸⁰ is independently H or CH₃; n¹ is 3, 4 or 5;R¹² is H or CH₃; R⁶ is C₁₋₄ alkyl optionally substituted with hydroxy;R⁸ is —CH₂-phenyl or —CH₂-naphthyl, wherein the phenyl is optionallysubstituted with one or more substituents each independently selectedfrom the group consisting of halogen, hydroxyl, and —NO₂; and L is

chiral centre *1 is in the S configuration; chiral centre *3 is in the Sconfiguration; chiral centre *4 is in the R configuration; chiral centre*5 is in the S configuration; chiral centre *6 is in the Sconfiguration; and chiral centre *8 is in the R configuration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula II or a salt thereof, wherein: R^(C) isOH or NH₂; R^(N) is H, CH₃ or acetyl; R¹ is —CH₂-phenyl or—CH₂-naphthyl, wherein the phenyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen and —NO₂; R³ is —CH₂-phenyl or —CH₂-pyridinyl, wherein thephenyl is optionally substituted with hydroxyl; R⁴ is

wherein R¹¹⁹ is phenyl, and n⁸ is 1; R⁵ is —NR⁷⁹R⁸⁰, wherein each of R⁷⁹and R⁸⁰ is independently H or CH₃; n¹ is 3, 4 or 5; R¹² is H or CH₃; R⁶is C₁₋₄ alkyl optionally substituted with hydroxy; R⁸ is —CH₂-phenyl or—CH₂-naphthyl, wherein the phenyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen, hydroxyl, and —NO₂; and L is

chiral centre *1 is in the S configuration; chiral centre *3 is in the Sconfiguration; chiral centre *4 is in the R configuration; chiral centre*5 is in the S configuration; chiral centre *6 is in the Sconfiguration; and chiral centre *8 is in the R configuration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula II or a salt thereof, wherein: R^(C) isOH or NH₂; R^(N) is H, CH₃ or acetyl; R¹ is —CH₂-phenyl or—CH₂-naphthyl, wherein the phenyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen and —NO₂; R³ is —CH₂-phenyl or —CH₂-pyridinyl, wherein thephenyl is optionally substituted with hydroxyl; R⁴ is

wherein each of R¹²⁶ and R¹²⁷ is independently selected from the groupconsisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl, wherein the C₁₋₆alkyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen, —OH, —NO₂, and C₁₋₆ alkoxy, and wherein the C₆₋₁₀ aryl and5- to 10-membered heteroaryl are optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein n⁹ is 1 or 2; R⁵ is—NR⁷⁹R⁸⁰, wherein each of R⁷⁹ and R⁸⁰ is independently H or CH₃; n¹ is3, 4 or 5; R¹² is H or CH₃; R⁶ is C₁₋₄ alkyl optionally substituted withhydroxy; R⁸ is —CH₂-phenyl or —CH₂-naphthyl, wherein the phenyl isoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, hydroxyl, and —NO₂; and Lis

chiral centre *1 is in the S configuration; chiral centre *3 is in the Sconfiguration; chiral centre *4 is in the R configuration; chiral centre*5 is in the S configuration; chiral centre *6 is in the Sconfiguration; and chiral centre *8 is in the R configuration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula II or a salt thereof, wherein: R^(C) isOH or NH₂; R^(N) is H, CH₃ or acetyl; R¹ is —CH₂-phenyl or—CH₂-naphthyl, wherein the phenyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen and —NO₂; R³ is —CH₂-phenyl or —CH₂-pyridinyl, wherein thephenyl is optionally substituted with hydroxyl; R⁴ is

wherein:

-   -   each of R¹³⁴ and R¹³⁵ is independently selected from the group        consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, 5- to 10-membered        heteroaryl, —C(O)R¹³⁶, and —C(O)NR¹³⁷R¹³⁸, wherein the C₁₋₆alkyl        is optionally substituted with one or more substituents each        independently selected from the group consisting of halogen,        —OH, —NO₂, and C₁₋₆ alkoxy, and wherein the C₆₋₁₀ aryl and 5- to        10-membered heteroaryl are optionally substituted with one or        more substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy, and wherein        n¹⁰ is 1 or 2, and wherein n¹¹ is 1 or 2;    -   R¹³⁶ is selected from the group consisting of C₁₋₆ alkyl, C₆₋₁₀        aryl, and 5- to 10-membered heteroaryl, wherein the C₁₋₆alkyl is        optionally substituted with one or more substituents each        independently selected from the group consisting of halogen,        —OH, —NO₂, and C₁₋₆ alkoxy, and wherein the C₆₋₁₀ aryl and 5- to        10-membered heteroaryl are optionally substituted with one or        more substituents each independently selected from the group        consisting of halogen, —OH, —NO₂, and C₁₋₆alkoxy; and    -   each of R¹³⁷ and R¹³⁸ is independently selected from the group        consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-membered        heteroaryl, wherein the C₁₋₆ alkyl is optionally substituted        with one or more substituents each independently selected from        the group consisting of halogen, —OH, —NO₂, and C₁₋₆ alkoxy, and        wherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are        optionally substituted with one or more substituents each        independently selected from the group consisting of halogen,        —OH, —NO₂, and C₁₋₆alkoxy;        R⁵ is —NR⁷⁹R⁸⁰, wherein each of R⁷⁹ and R⁸⁰ is independently H        or CH₃; n¹ is 3, 4 or 5; R¹² is H or CH₃; R⁶ is C₁₋₄ alkyl        optionally substituted with hydroxy; R⁸ is —CH₂-phenyl or        —CH₂-naphthyl, wherein the phenyl is optionally substituted with        one or more substituents each independently selected from the        group consisting of halogen, hydroxyl, and —NO₂; and L is

chiral centre *1 is in the S configuration; chiral centre *3 is in the Sconfiguration; chiral centre *4 is in the R configuration; chiral centre*5 is in the S configuration; chiral centre *6 is in the Sconfiguration; and chiral centre *8 is in the R configuration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula II or a salt thereof, wherein: R^(C) isOH or NH₂; R^(N) is H, CH₃ or acetyl; R¹ is —CH₂-phenyl or—CH₂-naphthyl, wherein the phenyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen and —NO₂; R³ is —CH₂-phenyl or —CH₂-pyridinyl, wherein thephenyl is optionally substituted with hydroxyl;

R⁴ is

wherein:

-   -   each of R¹³⁴ and R¹³⁵ is independently selected from the group        consisting of H, —C(O)R¹³⁶, and —C(O)NR¹³⁷R¹³⁸, and wherein n¹⁰        is 1, and wherein n¹¹ is 1; R¹³⁶ is selected from the group        consisting of C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-membered        heteroaryl, wherein the C₁₋₆alkyl is optionally substituted with        one or more substituents each independently selected from the        group consisting of halogen, —OH, —NO₂, and C₁₋₆ alkoxy, and        wherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are        optionally substituted with one or more substituents each        independently selected from the group consisting of halogen,        —OH, —NO₂, and C₁₋₆alkoxy; and    -   each of R¹³⁷ and R¹³⁸ is independently selected from the group        consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-membered        heteroaryl, wherein the C₁₋₆ alkyl is optionally substituted        with one or more substituents each independently selected from        the group consisting of halogen, —OH, —NO₂, and C₁₋₆ alkoxy, and        wherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are        optionally substituted with one or more substituents each        independently selected from the group consisting of halogen,        —OH, —NO₂, and C₁₋₆alkoxy;        R⁵ is —NR⁷⁹R⁸⁰, wherein each of R⁷⁹ and R⁸⁰ is independently H        or CH₃; n¹ is 3, 4 or 5; R¹² is H or CH₃; R⁶ is C₁₋₄ alkyl        optionally substituted with hydroxy; R⁸ is —CH₂-phenyl or        —CH₂-naphthyl, wherein the phenyl is optionally substituted with        one or more substituents each independently selected from the        group consisting of halogen, hydroxyl, and —NO₂; and L is

chiral centre *1 is in the S configuration; chiral centre *3 is in the Sconfiguration; chiral centre *4 is in the R configuration; chiral centre*5 is in the S configuration; chiral centre *6 is in the Sconfiguration; and chiral centre *8 is in the R configuration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula II or a salt thereof, wherein: R^(C) isOH or NH₂; R^(N) is H, CH₃ or acetyl; R¹ is —CH₂-phenyl or—CH₂-naphthyl, wherein the phenyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen and —NO₂; R³ is —CH₂-phenyl or —CH₂-pyridinyl, wherein thephenyl is optionally substituted with hydroxyl; R⁴ is n

wherein each of R¹³⁴ and R¹³⁵ is H, n¹⁰ is 1 and n¹¹ is 1; R⁵ is—NR⁷⁹R⁸⁰, wherein each of R⁷⁹ and R⁸⁰ is independently H or CH₃; n¹ is3, 4 or 5; R¹² is H or CH₃; R⁶ is C₁₋₄ alkyl optionally substituted withhydroxy; R⁸ is —CH₂-phenyl or —CH₂-naphthyl, wherein the phenyl isoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, hydroxyl, and —NO₂; and Lis

chiral centre *1 is in the S configuration; chiral centre *3 is in the Sconfiguration; chiral centre *4 is in the R configuration; chiral centre*5 is in the S configuration; chiral centre *6 is in the Sconfiguration; and chiral centre *8 is in the R configuration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula II or a salt thereof, wherein: R^(C) isOH or NH₂; R^(N) is H, CH₃ or acetyl; R¹ is —CH₂-phenyl or—CH₂-naphthyl, wherein the phenyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen and —NO₂; R³ is —CH₂-phenyl or —CH₂-pyridinyl, wherein thephenyl is optionally substituted with hydroxyl; R⁴ is

wherein R¹³⁴ is H, R¹³⁵ is —C(O)R¹³⁶, R¹³⁶ is C₁ alkyl, n¹⁰ is 1, andn¹¹ is 1; R⁵ is —NR⁷⁹R⁸⁰, wherein each of R⁷⁹ and R⁸⁰ is independently Hor CH₃; n¹ is 3, 4 or 5; R¹² is H or CH₃; R⁶ is C₁₋₄ alkyl optionallysubstituted with hydroxy; R⁸ is —CH₂-phenyl or —CH₂-naphthyl, whereinthe phenyl is optionally substituted with one or more substituents eachindependently selected from the group consisting of halogen, hydroxyl,and —NO₂; and L is

chiral centre *1 is in the S configuration; chiral centre *3 is in the Sconfiguration; chiral centre *4 is in the R configuration; chiral centre*5 is in the S configuration; chiral centre *6 is in the Sconfiguration; and chiral centre *8 is in the R configuration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula II or a salt thereof, wherein: R^(C) isOH or NH₂; R^(N) is H, CH₃ or acetyl; R¹ is —CH₂-phenyl or—CH₂-naphthyl, wherein the phenyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen and —NO₂; R³ is —CH₂-phenyl or —CH₂-pyridinyl, wherein thephenyl is optionally substituted with hydroxyl; R⁴ is

R¹³⁴ is H, R¹³⁵ is —C(O)NR¹³⁷R¹³⁸, each of R¹³⁷ and R¹³⁸ is H, n¹⁰ is 1,and n¹¹ is 1; R⁵ is —NR⁷⁹R⁸⁰, wherein each of R⁷⁹ and R⁸⁰ isindependently H or CH₃; n¹ is 3, 4 or 5; R¹² is H or CH₃; R⁶ is C₁₋₄alkyl optionally substituted with hydroxy; R⁸ is —CH₂-phenyl or—CH₂-naphthyl, wherein the phenyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen, hydroxyl, and —NO₂; and L is

chiral centre *1 is in the S configuration; chiral centre *3 is in the Sconfiguration; chiral centre *4 is in the R configuration; chiral centre*5 is in the S configuration; chiral centre *6 is in the Sconfiguration; and chiral centre *8 is in the R configuration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula II or a salt thereof, wherein: R^(C) isOH or NH₂; R^(N) is H, CH₃ or acetyl; R¹ is —CH₂-phenyl or—CH₂-naphthyl, wherein the phenyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen and —NO₂; R³ is —CH₂-phenyl or —CH₂-pyridinyl, wherein thephenyl is optionally substituted with hydroxyl; R⁴ is

wherein each of R¹⁴⁴ and R¹⁴⁵ is independently selected from the groupconsisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl, wherein the C₁₋₆alkyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen, —OH, —NO₂, C₁₋₆ alkoxy, and 5- to 10-memberedheterocycloalkyl, and wherein the C₆₋₁₀ aryl and 5- to 10-memberedheteroaryl are optionally substituted with one or more substituents eachindependently selected from the group consisting of halogen, —OH, —NO₂,C₁₋₆alkoxy, and 5- to 10-membered heterocycloalkyl, and wherein n¹² is 1or 2; R⁵ is —NR⁷⁹R⁸⁰, wherein each of R⁷⁹ and R⁸⁰ is independently H orCH₃; n¹ is 3, 4 or 5; R¹² is H or CH₃; R⁶ is C₁₋₄ alkyl optionallysubstituted with hydroxy; R⁸ is —CH₂-phenyl or —CH₂-naphthyl, whereinthe phenyl is optionally substituted with one or more substituents eachindependently selected from the group consisting of halogen, hydroxyl,and —NO₂; and L is

chiral centre *1 is in the S configuration; chiral centre *3 is in the Sconfiguration; chiral centre *4 is in the R configuration; chiral centre*5 is in the S configuration; chiral centre *6 is in the Sconfiguration; and chiral centre *8 is in the R configuration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula II or a salt thereof, wherein: R^(C) isOH or NH₂; R^(N) is H, CH₃ or acetyl; R¹ is —CH₂-phenyl or—CH₂-naphthyl, wherein the phenyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen and —NO₂; R³ is —CH₂-phenyl or —CH₂-pyridinyl, wherein thephenyl is optionally substituted with hydroxyl; R⁴ is

wherein each of R¹⁴⁴ and R¹⁴⁵ is independently selected from the groupconsisting of H and C₁₋₆ alkyl, wherein the C₁₋₆alkyl is optionallysubstituted with one or more substituents each independently selectedfrom the group consisting of 5- to 10-membered heterocycloalkyl,halogen, hydroxy, —NO₂, and C₁₋₆alkoxy, and n¹² is 1; R⁵ is —NR⁷⁹R⁸⁰,wherein each of R⁷⁹ and R⁸⁰ is independently H or CH₃; n¹ is 3, 4 or 5;R¹² is H or CH₃; R⁶ is C₁₋₄ alkyl optionally substituted with hydroxy;R⁸ is —CH₂-phenyl or —CH₂-naphthyl, wherein the phenyl is optionallysubstituted with one or more substituents each independently selectedfrom the group consisting of halogen, hydroxyl, and —NO₂; and L is

chiral centre *1 is in the S configuration; chiral centre *3 is in the Sconfiguration; chiral centre *4 is in the R configuration; chiral centre*5 is in the S configuration; chiral centre *6 is in the Sconfiguration; and chiral centre *8 is in the R configuration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula II or a salt thereof, wherein: R^(C) isOH or NH₂; R^(N) is H, CH₃ or acetyl; R¹ is —CH₂-phenyl or—CH₂-naphthyl, wherein the phenyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen and —NO₂; R³ is —CH₂-phenyl or —CH₂-pyridinyl, wherein thephenyl is optionally substituted with hydroxyl; R⁴ is

wherein R¹⁴⁴ is H and R¹⁴⁵ is C₁₋₆alkyl optionally substituted with oneor more substituents each independently selected from the groupconsisting of 5- to 10-membered heterocycloalkyl, halogen, hydroxy,—NO₂, and C₁₋₆alkoxy, and wherein n¹² is 1; R⁵ is —NR⁷⁹R⁸⁰, wherein eachof R⁷⁹ and R⁸⁰ is independently H or CH₃; n¹ is 3, 4 or 5; R¹² is H orCH₃; R⁶ is C₁₋₄ alkyl optionally substituted with hydroxy; R⁸ is—CH₂-phenyl or —CH₂-naphthyl, wherein the phenyl is optionallysubstituted with one or more substituents each independently selectedfrom the group consisting of halogen, hydroxyl, and —NO₂; and L is

chiral centre *1 is in the S configuration; chiral centre *3 is in the Sconfiguration; chiral centre *4 is in the R configuration; chiral centre*5 is in the S configuration; chiral centre *6 is in the Sconfiguration; and chiral centre *8 is in the R configuration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula II or a salt thereof, wherein: R^(C) isOH or NH₂; R^(N) is H, CH₃ or acetyl; R¹ is —CH₂-phenyl or—CH₂-naphthyl, wherein the phenyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen and —NO₂; R³ is —CH₂-phenyl or —CH₂-pyridinyl, wherein thephenyl is optionally substituted with hydroxyl; R⁴ is

wherein R¹⁴⁴ is H and R¹⁴⁵ is C₂ alkyl substituted with morpholinyl, andwherein n¹² is 1; R⁵ is —NR⁷⁹R⁸⁰, wherein each of R⁷⁹ and R⁸⁰ isindependently H or CH₃; n¹ is 3, 4 or 5; R¹² is H or CH₃; R⁶ is C₁₋₄alkyl optionally substituted with hydroxy; R⁸ is —CH₂-phenyl or—CH₂-naphthyl, wherein the phenyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen, hydroxyl, and —NO₂; and L is

chiral centre *1 is in the S configuration; chiral centre *3 is in the Sconfiguration; chiral centre *4 is in the R configuration; chiral centre*5 is in the S configuration; chiral centre *6 is in the Sconfiguration; and chiral centre *8 is in the R configuration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula II or a salt thereof, wherein: R^(C) isOH or NH₂; R^(N) is H, CH₃ or acetyl; R¹ is —CH₂-phenyl or—CH₂-naphthyl, wherein the phenyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen and —NO₂; R³ is —CH₂-phenyl or —CH₂-pyridinyl, wherein thephenyl is optionally substituted with hydroxyl; R⁴ is

wherein R¹⁴⁴ is H and R¹⁴⁵ is C₅ alkyl, and wherein n¹² is 1; R⁵ is—NR⁷⁹R⁸⁰, wherein each of R⁷⁹ and R⁸⁰ is independently H or CH₃; n¹ is3, 4 or 5; R¹² is H or CH₃; R⁶ is C₁₋₄ alkyl optionally substituted withhydroxy; R⁸ is —CH₂-phenyl or —CH₂-naphthyl, wherein the phenyl isoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, hydroxyl, and —NO₂; and Lis

chiral centre *1 is in the S configuration; chiral centre *3 is in the Sconfiguration; chiral centre *4 is in the R configuration; chiral centre*5 is in the S configuration; chiral centre *6 is in the Sconfiguration; and chiral centre *8 is in the R configuration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula II or a salt thereof, wherein: R^(C) isOH or NH₂; R^(N) is H, CH₃ or acetyl; R¹ is —CH₂-phenyl or—CH₂-naphthyl, wherein the phenyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen and —NO₂; R³ is —CH₂-phenyl or —CH₂-pyridinyl, wherein thephenyl is optionally substituted with hydroxyl; R⁴ is

wherein R¹⁴⁶ is selected from the group consisting of H, C₁₋₆alkyl,C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the C₁₋₆alkyl isoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, —OH, —NO₂, C₁₋₆alkoxy,and 5- to 10-membered heterocycloalkyl, and wherein the C₆₋₁₀ aryl and5- to 10-membered heteroaryl are optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen, —OH, —NO₂, C₁₋₆alkoxy, and 5- to 10-membered heterocycloalkyl,and wherein n¹³ is 1 or 2; and R⁵ is —NR⁷⁹R⁸⁰, wherein each of R⁷⁹ andR⁸⁰ is independently H or CH₃; n¹ is 3, 4 or 5; R¹² is H or CH₃; R⁶ isC₁₋₄ alkyl optionally substituted with hydroxy; R⁸ is —CH₂-phenyl or—CH₂— naphthyl, wherein the phenyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen, hydroxyl, and —NO₂; and L is

chiral centre *1 is in the S configuration; chiral centre *3 is in the Sconfiguration; chiral centre *4 is in the R configuration; chiral centre*5 is in the S configuration; chiral centre *6 is in the Sconfiguration; and chiral centre *8 is in the R configuration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula II or a salt thereof, wherein: R^(C) isOH or NH₂; R^(N) is H, CH₃ or acetyl; R is —CH₂-phenyl or —CH₂-naphthyl,wherein the phenyl is optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen and —NO₂; R³ is —CH₂-phenyl or —CH₂-pyridinyl, wherein thephenyl is optionally substituted with hydroxyl; R⁴ is

wherein R¹⁴⁶ is C₁₋₆alkyl optionally substituted with one or moresubstituents each independently selected from the group consisting of 5-to 10-membered heterocycloalkyl, halogen, hydroxy, —NO₂, and C₁₋₆alkoxy,and wherein n¹³ is 1; and R⁵ is —NR⁷⁹R⁸¹, wherein each of R⁷⁹ and R⁸⁰ isindependently H or CH₃; n¹ is 3, 4 or 5; R¹² is H or CH₃; R⁶ is C₁₋₄alkyl optionally substituted with hydroxy; R⁸ is —CH₂-phenyl or—CH₂-naphthyl, wherein the phenyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen, hydroxyl, and —NO₂; and L is

chiral centre *1 is in the S configuration; chiral centre *3 is in the Sconfiguration; chiral centre *4 is in the R configuration; chiral centre*5 is in the S configuration; chiral centre *6 is in the Sconfiguration; and chiral centre *8 is in the R configuration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula II or a salt thereof, wherein: R^(C) isOH or NH₂; R^(N) is H, CH₃ or acetyl; R¹ is —CH₂-phenyl or—CH₂-naphthyl, wherein the phenyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen and —NO₂; R³ is —CH₂-phenyl or —CH₂-pyridinyl, wherein thephenyl is optionally substituted with hydroxyl; R⁴ is

wherein R¹⁴⁶ is C₂ alkyl substituted with morpholinyl, and wherein n¹³is 1; R⁵ is —NR⁷⁹R⁸⁰, wherein each of R⁷⁹ and R⁸⁰ is independently H orCH₃; n¹ is 3, 4 or 5; R¹² is H or CH₃; R⁶ is C₁₋₄ alkyl optionallysubstituted with hydroxy; R⁸ is —CH₂-phenyl or —CH₂-naphthyl, whereinthe phenyl is optionally substituted with one or more substituents eachindependently selected from the group consisting of halogen, hydroxyl,and —NO₂; and L is

chiral centre *1 is in the S configuration; chiral centre *3 is in the Sconfiguration; chiral centre *4 is in the R configuration; chiral centre*5 is in the S configuration; chiral centre *6 is in the Sconfiguration; and chiral centre *8 is in the R configuration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula II or a salt thereof, wherein: R^(C) isOH or NH₂; R^(N) is H, CH₃ or acetyl; R¹ is —CH₂-phenyl or—CH₂-naphthyl, wherein the phenyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen and —NO₂; R³ is —CH₂-phenyl or —CH₂-pyridinyl, wherein thephenyl is optionally substituted with hydroxyl; R⁴ is

wherein R¹⁴⁸ is H or CH₃, R¹⁴⁹ is H or C₁₋₆ alkyl optionally substitutedwith one or more substituents each independently selected from the groupconsisting of hydroxyl, —COOH, —NH₂, —C(O)NH₂, and —N(H)C(O)NH₂, andR¹⁵⁰ is H, CH₃ or acetyl, and wherein n¹⁴ is 1 or 2; R⁵ is —NR⁷⁹R⁸⁰,wherein each of R⁷⁹ and R⁸⁰ is independently H or CH₃; n¹ is 3, 4 or 5;R¹² is H or CH₃; R⁶ is C₁₋₄ alkyl optionally substituted with hydroxy;R⁸ is —CH₂-phenyl or —CH₂-naphthyl, wherein the phenyl is optionallysubstituted with one or more substituents each independently selectedfrom the group consisting of halogen, hydroxyl, and —NO₂; and L is

chiral centre *1 is in the S configuration; chiral centre *3 is in the Sconfiguration; chiral centre *4 is in the R configuration; chiral centre*5 is in the S configuration; chiral centre *6 is in the Sconfiguration; and chiral centre *8 is in the R configuration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula II or a salt thereof, wherein: R^(C) isOH or NH₂; R^(N) is H, CH₃ or acetyl; R¹ is —CH₂-phenyl or—CH₂-naphthyl, wherein the phenyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen and —NO₂; R³ is —CH₂-phenyl or —CH₂-pyridinyl, wherein thephenyl is optionally substituted with hydroxyl; R⁴ is

wherein R¹⁴⁸ is H, R¹⁴⁹ is H, and R¹⁵⁰ is H or acetyl, and wherein n¹⁴is 1; R⁵ is —NR⁷⁹R⁸⁰, wherein each of R⁷⁹ and R⁸⁰ is independently H orCH₃; n¹ is 3, 4 or 5; R¹² is H or CH₃; R⁶ is C₁₋₄ alkyl optionallysubstituted with hydroxy; R⁸ is —CH₂-phenyl or —CH₂-naphthyl, whereinthe phenyl is optionally substituted with one or more substituents eachindependently selected from the group consisting of halogen, hydroxyl,and —NO₂; and L is

chiral centre *1 is in the S configuration; chiral centre *3 is in the Sconfiguration; chiral centre *4 is in the R configuration; chiral centre*5 is in the S configuration; chiral centre *6 is in the Sconfiguration; and chiral centre *8 is in the R configuration.

Illustrative embodiments of the present invention include a compoundhaving the structure of Formula II or a salt thereof, wherein: R^(C) isOH or NH₂; R^(N) is H, CH₃ or acetyl; R¹ is —CH₂-phenyl or—CH₂-naphthyl, wherein the phenyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen and —NO₂; R³ is —CH₂-phenyl or —CH₂-pyridinyl, wherein thephenyl is optionally substituted with hydroxyl; R⁴ is

wherein R¹⁴⁸ is H, R¹⁴⁹ is C₁₋₆ alkyl optionally substituted with one ormore substituents each independently selected from the group consistingof hydroxyl, —COOH, —NH₂, —C(O)NH₂, and —N(H)C(O)NH₂, and R¹⁵⁰ is H, andwherein n¹⁴ is 1; R⁵ is —NR⁷⁹R⁸⁰, wherein each of R⁷⁹ and R⁸⁰ isindependently H or CH₃; n¹ is 3, 4 or 5; R¹² is H or CH₃; R⁶ is C₁₋₄alkyl optionally substituted with hydroxy; R⁸ is —CH₂-phenyl or—CH₂-naphthyl, wherein the phenyl is optionally substituted with one ormore substituents each independently selected from the group consistingof halogen, hydroxyl, and —NO₂; and L is

chiral centre *1 is in the S configuration; chiral centre *3 is in the Sconfiguration; chiral centre *4 is in the R configuration; chiral centre*5 is in the S configuration; chiral centre *6 is in the Sconfiguration; and chiral centre *8 is in the R configuration.

In certain embodiments, the compound may be selected from Table 5 andsalts thereof. In certain embodiments, the compound may be selectedfrom: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19,20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37,38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55,56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 67, 69, 70, 71, 72, 73,74, 75, 76, 77, 78, 79, 80, 81, and 82, and salts thereof. In certainembodiments, the compound may be selected from: 1, 2, 3, 4, 5, 6, 7, 8,9, 11, 12, 13, 14, 15, 16, 20, 22, 23, 24, 25, 27, 28, 29, 30, 31, 32,33, 34, 35, 36, 37, 38, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51,52, 53, 54, 55, 56, 57, 58, 59, 65, 71, 72, 73, 74, 76, 77, 78, and 79,and salts thereof. In certain embodiments, the compound may be selectedfrom: 1, 2, 3, 4, 5, 6, 7, 8, 9, 11, 12, 13, 14, 15, 16, 22, 23, 24, 25,27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 40, 41, 42, 43, 44, 45,46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 71, 72, 74, 76,77, 78, and 79, and salts thereof. In certain embodiments, the compoundmay be selected from: 1, 4, 7, 8, 12, 14, 15, 24, 25, 27, 31, 32, 33,34, 35, 36, 37, 38, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52,53, 54, 55, 56, 57, 58, 59, 71, 72, 77, 78, and 79, and salts thereof.In certain embodiments, the compound may be selected from: 1, 4, 7, 12,14, 15, 24, 25, 27, 32, 34, 35, 36, 37, 38, 40, 41, 42, 43, 44, 45, 46,47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 71, 72, 77, 78, and79, and salts thereof. In certain embodiments, the compound may beselected from: 15, 24, 25, 32, 42, 46, 47, 48, 49, 50, 51, 52, 53, 54,55, 56, 57, 58, 72, 77, and 78, and salts thereof. In certainembodiments, the compound may be selected from: 1, 4, 7, 8, 12, 14, 15,24, 31, 32, 33, 34, 35, 36, 37, 38, 43, 46, 47, 48, 49, 50, 51, 52, 53,54, 55, 56, 57, 58, 59, 71, 72, 77, 78, and 79, and salts thereof. Incertain embodiments, the compound may be selected from: 1, 4, 7, 12, 14,15, 24, 32, 34, 35, 36, 37, 38, 43, 46, 47, 48, 49, 50, 51, 52, 53, 54,55, 56, 57, 58, 59, 71, 72, 77, 78, and 79, and salts thereof. Incertain embodiments, the compound may be selected from: 15, 24, 32, 46,47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 72, 77, and 78, andsalts thereof. In certain embodiments, the compound may be selectedfrom: 15, 24, 32, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58,and 77, and salts thereof. In certain embodiments, the compound may beselected from: 15, 24, 25, 32, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55,56, 57, 58, and 77, and salts thereof. In certain embodiments, thecompound may be selected from: 15, 24, 46, 47, 48, 50, 51, 52, and 56,and salts thereof. In certain embodiments, the compound may be selectedfrom: 24 and 46, and salts thereof. In certain embodiments, the compoundmay be selected from: 4 and 24, and salts thereof.

In embodiments of the cyclic peptides where cysteine residues are joinedby a cyclizing disulfide bond, those of ordinary skill in the art willappreciate that the compounds may also be depicted using the notation:R^(N)N(H)-Xaa¹-cyclo[DCys-Xaa³-Xaa⁴-Xaa⁵-Xaa⁶-Cys]-Xaa⁸-R^(C) orRNN(H)-Xaa¹-(Cys-Cys bridge)[DCys-Xaa³-Xaa⁴-Xaa⁵-Xaa⁶-Cys]-Xaa⁸-R^(C)using terminology or abbreviations commonly used in the art and theannotation “(Cys-Cys bridge)” or “cyclo[ ]” for the disulfide bondlinkage. For example, the compound having the structure:

may also be depicted as H-Cpa-cyclo[DCys-Tyr-DCit-Lys-Thr-Cys]-DTyr-NH₂or H-Cpa-(Cys-Cys bridge)[DCys-Tyr-DCit-Lys-Thr-Cys]-DTyr-NH₂.

Other embodiments where the peptides are cyclized with linkages otherthan a disulfide bond linking cysteine residues may be depicted asRNN(H)-Xaa¹-(L′ bridge)[Xaa²-Xaa³-Xaa⁴-Xaa⁵-Xaa⁶-Xaa⁷]-Xaa⁸-R^(C) usingterminology or abbreviations commonly used in the art and the annotation“(L′ bridge)” for the cyclizing linkage where L′ indicates the type oflinkage. Terminology or abbreviations commonly used in the art include,but are not limited to, those listed in the table below.

Abbreviations

-   4Aph(Cbm): 4-ureido-phenylalanine-   4Aph(Hor):    4-[(2,6-dioxo-hexahydro-pyrimidine-4-carbonyl)-amino]-phenylalanine-   2,4-dichloro-Phe: 3-[2,4-dichlorophenyl]-alanine-   1-Nal: 3-(1-naphthyl)alanine-   2Fpa: 2-fluorophenylalanine-   2-Nal: 3-(2-naphthyl)alanine-   2-Pal: [2-pyridyl]-alanine or 3-(2-pyridyl)alanine-   2-Pal: β-[2-pyridyl]-alanine,-   3Fpa: 3-fluorophenylalanine-   3-Pal: 3-(3-pyridyl)alanine-   4-Pal: 3-(4-pyridyl)alanine-   Abu: 2-aminobutyric acid or α-aminobutyric acid-   Ahp: 7-aminoheptanoic acid-   Aib: 2-aminoisobutyric acid or α-aminoisobutyric acid-   Amp: 4-amino-phenylalanine-   Ava: 5-aminovaleric acid-   β-Ala: β-alanine or 3-aminopropionic acid-   β-Nal: β-[1-naphthyl]-alanine-   β-Nal: β-[2-napthyl]-alanine-   Bip: biphenylalanine or 4,4′-biphenylalanine-   Bpa: 4-bromophenylalanine-   Bta: benzothienylalanine or 3-benzothienylalanine-   Cha: cyclohexylalanine or 3-(cyclohexyl)-alanine-   Cit: citrulline-   Cpa: 3-(4-chlorophenyl)alanine or β-[4-chlorophenyl]-alanine-   Dab: 2,4-diaminobutyric acid-   Dap: 2,3-diaminopropionic acid-   Dip: 3,3′-diphenylalanine-   F₅-Phe: 2,3,4,5,6-pentafluorophenyl]-alanine or    3-[2,3,4,5,6-pentafluorophenyl]-alanine-   Fpa: 4-fluorophenylalanine-   Gaba: γ-aminobutyric acid or 4-aminobutyric acid-   HSer or HoSer: homoserine-   HoCit or HCit: homocitrulline-   HoLys or HLys: homolysine-   HoCys or HCys: homocysteine-   Igl: 2-indanylglycine-   Iph: 4-iodophenylalanine-   Nal: 3-(2-naphthyl)alanine-   Nle: norleucine-   Npa or pNO₂-Phe: 4-nitrophenylalanine or p-NO₂-phenylalanine-   Nva: norvaline-   Pal: 3-pyridylalanine or β-[3-pyridyl]-alanine-   Pen: peniciliamine-   Tba: tert-butylalanine-   TfmA: 4-trifluoromethylphenyl-alanine-   Thr(Bzl): O-benzyl-threonine-   Tic: 1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid-   Tle: tert-leucine or α-[t-butyl]-glycine-   Tyr(Bzl): O-benzyl-tyrosine-   Tyr(I) or ITyr: an iodinated tyrosine residue (e.g., 3-I-Tyr,    5-I-Tyr, 3,5-I-Tyr)-   Ypa: 4-cyanophenylalanine

Unless specified, the trivial name or symbol refers to the L-amino acid.

In one aspect, the invention provides compounds of Formula I exhibitingSSTR2 binding activity. In one aspect the invention provides compoundsof Formula II exhibiting SSTR2 binding activity. Determination of SSTR2binding activity is routine and well within the capability of theartisan of reasonable skill in the art. For example, competitive bindingassays using SSTR2 and a known SSTR2 ligand, for example SST or acompound exemplified below (for example, compound 24) may be performedto determine SSTR2 binding activity of a subject compound.

In one aspect, the invention provides compounds of Formula I exhibitingSSTR2 antagonistic activity. In one aspect the invention providescompounds of Formula II exhibiting SSTR2 antagonistic activity.Determination of SSTR2 antagonistic activity is routine and well withinthe capability of the artisan of reasonable skill in the art. Forexample, SSTR2 activity assays using SSTR2-expressing cells and a knownSSTR2 agonist, for example SST, may be performed to determine SSTR2antagonist activity of a subject compound. In one embodiment, a controlSSTR2 antagonist compound may be used (for example, compound 24).

Compounds as described herein may be in the free form or in the form ofa salt thereof. In some embodiments, compounds as described herein maybe in the form of a pharmaceutically acceptable salt, which are known inthe art (Berge et al., J. Pharm. Sci. 1977, 66, 1). Pharmaceuticallyacceptable salt as used herein includes, for example, salts that havethe desired pharmacological activity of the parent compound (salts whichretain the biological effectiveness and/or properties of the parentcompound and which are not biologically and/or otherwise undesirable).Compounds as described herein having one or more functional groupscapable of forming a salt may be, for example, formed as apharmaceutically acceptable salt. Compounds containing one or more basicfunctional groups may be capable of forming a pharmaceuticallyacceptable salt with, for example, a pharmaceutically acceptable organicor inorganic acid. Pharmaceutically acceptable salts may be derivedfrom, for example, and without limitation, acetic acid, adipic acid,alginic acid, aspartic acid, ascorbic acid, benzoic acid,benzenesulfonic acid, butyric acid, cinnamic acid, citric acid,camphoric acid, camphorsulfonic acid, cyclopentanepropionic acid,diethylacetic acid, digluconic acid, dodecylsulfonic acid,ethanesulfonic acid, formic acid, fumaric acid, glucoheptanoic acid,gluconic acid, glycerophosphoric acid, glycolic acid, hemisulfonic acid,heptanoic acid, hexanoic acid, hydrochloric acid, hydrobromic acid,hydriodic acid, 2-hydroxyethanesulfonic acid, isonicotinic acid, lacticacid, malic acid, maleic acid, malonic acid, mandelic acid,methanesulfonic acid, 2-napthalenesulfonic acid, naphthalenedisulphonicacid, p-toluenesulfonic acid, nicotinic acid, nitric acid, oxalic acid,pamoic acid, pectinic acid, 3-phenylpropionic acid, phosphoric acid,picric acid, pimelic acid, pivalic acid, propionic acid, pyruvic acid,salicylic acid, succinic acid, sulfuric acid, sulfamic acid, tartaricacid, thiocyanic acid or undecanoic acid. Compounds containing one ormore acidic functional groups may be capable of forming pharmaceuticallyacceptable salts with a pharmaceutically acceptable base, for example,and without limitation, inorganic bases based on alkaline metals oralkaline earth metals or organic bases such as primary amine compounds,secondary amine compounds, tertiary amine compounds, quaternary aminecompounds, substituted amines, naturally occurring substituted amines,cyclic amines or basic ion-exchange resins. Pharmaceutically acceptablesalts may be derived from, for example, and without limitation, ahydroxide, carbonate, or bicarbonate of a pharmaceutically acceptablemetal cation such as ammonium, sodium, potassium, lithium, calcium,magnesium, iron, zinc, copper, manganese or aluminum, ammonia,benzathine, meglumine, methylamine, dimethylamine, trimethylamine,ethylamine, diethylamine, triethylamine, isopropylamine, tripropylamine,tributylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol,2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine,caffeine, hydrabamine, choline, betaine, ethylenediamine, glucosamine,glucamine, methylglucamine, theobromine, purines, piperazine,piperidine, procaine, N-ethylpiperidine, theobromine,tetramethylammonium compounds, tetraethylammonium compounds, pyridine,N,N-dimethylaniline, N-methylpiperidine, morpholine, N-methylmorpholine,N-ethylmorpholine, dicyclohexylamine, dibenzylamine,N,N-dibenzylphenethylamine, 1-ephenamine, N,N′-dibenzylethylenediamineor polyamine resins. In some embodiments, compounds as described hereinmay contain both acidic and basic groups and may be in the form of innersalts or zwitterions, for example, and without limitation, betaines.Salts as described herein may be prepared by conventional processesknown to a person skilled in the art, for example, and withoutlimitation, by reacting the free form with an organic acid or inorganicacid or base, or by anion exchange or cation exchange from other salts.Those skilled in the art will appreciate that preparation of salts mayoccur in situ during isolation and purification of the compounds orpreparation of salts may occur by separately reacting an isolated andpurified compound.

In some embodiments, compounds and all different forms thereof (e.g.free forms, salts, polymorphs, isomeric forms) as described herein maybe in the solvent addition form, for example, solvates. Solvates containeither stoichiometric or non-stoichiometric amounts of a solvent inphysical association the compound or salt thereof. The solvent may be,for example, and without limitation, a pharmaceutically acceptablesolvent. For example, hydrates are formed when the solvent is water oralcoholates are formed when the solvent is an alcohol.

In some embodiments, compounds and all different forms thereof (e.g.free forms, salts, solvates, isomeric forms) as described herein mayinclude crystalline and amorphous forms, for example, polymorphs,pseudopolymorphs, conformational polymorphs, amorphous forms, or acombination thereof. Polymorphs include different crystal packingarrangements of the same elemental composition of a compound. Polymorphsusually have different X-ray diffraction patterns, infrared spectra,melting points, density, hardness, crystal shape, optical and electricalproperties, stability and/or solubility. Those skilled in the art willappreciate that various factors including recrystallization solvent,rate of crystallization and storage temperature may cause a singlecrystal form to dominate.

In some embodiments, compounds and all different forms thereof (e.g.free forms, salts, solvates, polymorphs) as described herein includeisomers such as geometrical isomers, optical isomers based on asymmetriccarbon, stereoisomers, tautomers, individual enantiomers, individualdiastereomers, racemates, diastereomeric mixtures and combinationsthereof, and are not limited by the description of the formulaillustrated for the sake of convenience.

In some embodiments, the compounds of the present invention or theirpharmaceutically acceptable salts may be for use in the prevention ortreatment of hypoglycemia. In some embodiments, the hypoglycemia isinsulin-induced hypoglycemia. In other embodiments, the compounds of thepresent invention or their pharmaceutically acceptable salts may be foruse in the treatment of diabetes. In other embodiments, the compounds ofthe present invention or their pharmaceutically acceptable salts may befor use in increasing release of insulin in a subject.

In accordance with another embodiment of the present invention, there isprovided a pharmaceutical composition comprising a compound of thepresent invention or a pharmaceutically acceptable salt thereof and apharmaceutically acceptable carrier.

In one aspect, the invention provides a pharmaceutical compositioncomprising a compound of the present invention or a pharmaceuticallyacceptable salt thereof, a second agent, and a pharmaceuticallyacceptable carrier. In one embodiment, the second agent is an agentuseful in the treatment of diabetes. In one embodiment, the second agentis insulin or an insulin analog.

Pharmaceutical compositions will typically comprise one or morecarriers, excipients or diluents acceptable for the mode ofadministration of the preparation, be it by injection, inhalation,topical administration, lavage, oral, sublingual, transmucosal,transdermal, rectal, vaginal, subcutaneous, intramuscular, intravenous,intra-arterial, intrathecal, via catheter, via implant, or other modessuitable for the selected treatment. Suitable carriers, excipients ordiluents are those known in the art for use in such modes ofadministration.

Suitable pharmaceutical compositions may be formulated by means known inthe art and their mode of administration and dose determined by theskilled practitioner. For parenteral administration, a compound may bedissolved in sterile water or saline or a pharmaceutically acceptablevehicle used for administration of non-water soluble compounds such asthose used for vitamin K. For enteral administration, the compound maybe administered in a tablet, capsule or dissolved in liquid form. Thetablet or capsule may be enteric coated, or in a formulation forsustained release. Many suitable formulations are known, including,polymeric or protein microparticles encapsulating a compound to bereleased, ointments, pastes, gels, hydrogels, or solutions which can beused topically or locally to administer a compound. A sustained releasepatch or implant may be employed to provide release over a prolongedperiod of time. Many techniques known to one of skill in the art aredescribed in Remington: the Science & Practice of Pharmacy by AlfonsoGennaro, 20^(th) ed., Lippencott Williams & Wilkins, (2000).Formulations for parenteral administration may, for example, containexcipients, polyalkylene glycols such as polyethylene glycol, oils ofvegetable origin, or hydrogenated naphthalenes. Biocompatible,biodegradable lactide polymer, lactide/glycolide copolymer, orpolyoxyethylene-polyoxypropylene copolymers may be used to control therelease of the compounds. Other potentially useful parenteral deliverysystems for modulatory compounds include ethylene-vinyl acetatecopolymer particles, osmotic pumps, implantable infusion systems, andliposomes. Formulations for inhalation may contain excipients, forexample, lactose, or may be aqueous solutions containing, for example,polyoxyethylene-9-lauryl ether, glycocholate and deoxycholate, or may beoily solutions for administration in the form of nasal drops, or as agel. The formulations may be specifically prepared for intranasaldelivery. For example, nasal inhalation. Formulations for subcutaneousadministration may comprise, for example, glycerol, α-tocopherolpolyethylene glycol succinate (TPGS) and a buffer.

Compounds or pharmaceutical compositions in accordance with thisinvention or for use in this invention may be administered by means of amedical device or appliance such as an implant, graft, prosthesis,stent, etc. Also, implants may be devised which are intended to containand release such compounds or compositions. An example would be animplant made of a polymeric material adapted to release the compoundover a period of time.

The compounds of the present invention or pharmaceutically acceptablesalts thereof, or compositions may be contained in pharmaceutical kitsor packs. In those embodiments in which the compounds of the presentinvention are intended for use as part of a combination therapy, the kitmay optionally contain the other therapeutic agents that make up thecombination. For example, pharmaceutical kits and packs comprisingcompounds of the present invention may further comprise a therapeuticagent useful in the treatment of diabetes. In one embodiment, thetherapeutic agent is insulin or an insulin analog. Individual componentsof the kit may be packaged in separate containers and, associated withsuch containers, can be a notice in the form prescribed by agovernmental agency regulating the manufacture, use or sale ofpharmaceuticals or biological products, which notice reflects approvalby the agency of manufacture, for use or sale for human or animaladministration. In those embodiments in which the compound of thepresent invention, is included in the kit in the form of apharmaceutical composition suitable for administration to a subject, thecontainer may optionally be itself in a form allowing for administrationto a subject, for example, an inhaler, syringe, pipette, eye dropper,pre-soaked gauze or pad, or other such like apparatus, from which thecomposition may be administered to the subject.

There are also provided drug conjugates comprising a compound of thepresent invention as defined anywhere herein or a pharmaceuticallyacceptable salt thereof.

Method or Uses

The compositions of the invention, including the cyclic peptides of theinvention and pharmaceutical compositions of the invention, have a widerange of uses.

In some embodiments, the cyclic peptides or pharmaceutical compositionsmay be for use in the prevention or treatment of hypoglycemia. In someembodiments, the hypoglycemia is insulin-induced hypoglycemia. In someembodiments, the cyclic peptide or pharmaceutical composition may be foruse in the treatment of diabetes. In some embodiments, the cyclicpeptide or pharmaceutical composition may be for use in increasingrelease of insulin in a subject.

In accordance with another embodiment, there is provided a method ofinhibiting an activity of an SSTR2 receptor in a subject, the methodcomprising administering a compound of the present invention orpharmaceutically acceptable salt thereof, to a subject in need thereof.In another embodiment, there is provided a method of preventing ortreating hypoglycemia in a subject, the method comprising administeringa compound of the present invention or a pharmaceutically acceptablesalt thereof, to a subject in need thereof. In some embodiments, thehypoglycemia is insulin-induced hypoglycemia. In accordance with anotherembodiment, there is provided a method of treating diabetes in asubject, the method comprising administering a compound of the presentinvention, or a pharmaceutically acceptable salt thereof, to a subjectin need thereof. In a further embodiment, there is provided a method ofincreasing insulin release in a subject, the method comprisingadministering a compound of the present invention, or a pharmaceuticallyacceptable salt thereof, to a subject in need thereof.

In accordance with a further embodiment, there is provided a use of acompound of the present invention or a pharmaceutically acceptable saltthereof for the prevention or treatment of hypoglycemia. In someembodiments, the hypoglycemia is insulin-induced hypoglycemia. In otherembodiments, there is provided a use of a compound of the presentinvention or a pharmaceutically acceptable salt thereof in the treatmentof diabetes. In other embodiments, there is provided a use of a compoundof the present invention or a pharmaceutically acceptable salt thereoffor increasing release of insulin in a subject. In still anotherembodiment, there is provided a use of a compound of the presentinvention or a pharmaceutically acceptable salt thereof in thepreparation of a medicament for the prevention or treatment ofhypoglycemia. In some embodiments, the hypoglycemia is insulin-inducedhypoglycemia. In further embodiments, there is provided a use a compoundof the present invention or a pharmaceutically acceptable salt thereofin the preparation of a medicament for the treatment of diabetes. Inaccordance with another embodiment, there is provided a use of acompound of the present invention or a pharmaceutically acceptable saltthereof in the preparation of a medicament for increasing the release ofinsulin in a subject.

In one aspect, the invention provides a method for decreasing theseverity of hypoglycemia in a subject, the method comprisingadministering a compound of the present invention or pharmaceuticallyacceptable salt thereof, to the subject. In one embodiment, the subjecthas diabetes. In one embodiment, the method involves coadministration ofa compound of the present invention or pharmaceutically acceptable saltthereof with a second agent useful in the treatment of diabetes. In oneembodiment, the second agent is linsulin or an insulin analog.

In one aspect, the invention provides a method for preventinghypoglycemia in a subject, the method comprising administering acompound of the present invention or pharmaceutically acceptable saltthereof, to the subject. In one embodiment, the subject has diabetes. Inone embodiment, the method involves coadministration of a compound ofthe present invention or pharmaceutically acceptable salt thereof with asecond agent useful in the treatment of diabetes. In one embodiment, thesecond agent is linsulin or an insulin analog.

In one aspect, the invention provides a method for preventing severehypoglycemia in a subject, the method comprising administering acompound of the present invention or pharmaceutically acceptable saltthereof, to the subject. In one embodiment, the subject has diabetes. Inone embodiment, the method involves coadministration of a compound ofthe present invention or pharmaceutically acceptable salt thereof with asecond agent useful in the treatment of diabetes. In one embodiment, thesecond agent is linsulin or an insulin analog.

In one aspect, the invention provides a method for decreasing theduration of hypoglycemia in a subject, the method comprisingadministering a compound of the present invention or pharmaceuticallyacceptable salt thereof, to the subject. In one embodiment, the subjecthas diabetes. In one embodiment, the method involves coadministration ofa compound of the present invention or pharmaceutically acceptable saltthereof with a second agent useful in the treatment of diabetes. In oneembodiment, the second agent is linsulin or an insulin analog.

In one aspect, the invention provides a method for decreasing theduration of severe hypoglycemia in a subject, the method comprisingadministering a compound of the present invention or pharmaceuticallyacceptable salt thereof, to the subject. In one embodiment, the subjecthas diabetes. In one embodiment, the method involves coadministration ofa compound of the present invention or pharmaceutically acceptable saltthereof with a second agent useful in the treatment of diabetes. In oneembodiment, the second agent is linsulin or an insulin analog.

In one aspect, the invention provides a method for decreasing theprobability of hypoglycemia in a subject, the method comprisingadministering a compound of the present invention or pharmaceuticallyacceptable salt thereof, to the subject. In one embodiment, the subjecthas diabetes. In one embodiment, the method involves coadministration ofa compound of the present invention or pharmaceutically acceptable saltthereof with a second agent useful in the treatment of diabetes. In oneembodiment, the second agent is linsulin or an insulin analog.

In one aspect, the invention provides a method for decreasing theprobability of severe hypoglycemia in a subject, the method comprisingadministering a compound of the present invention or pharmaceuticallyacceptable salt thereof, to the subject. In one embodiment, the subjecthas diabetes. In one embodiment, the method involves coadministration ofa compound of the present invention or pharmaceutically acceptable saltthereof with a second agent useful in the treatment of diabetes. In oneembodiment, the second agent is linsulin or an insulin analog.

In one aspect, the invention provides a method for delaying the onset ofhypoglycemia in a subject, the method comprising administering acompound of the present invention or pharmaceutically acceptable saltthereof, to the subject. In one embodiment, the subject has diabetes. Inone embodiment, the method involves coadministration of a compound ofthe present invention or pharmaceutically acceptable salt thereof with asecond agent useful in the treatment of diabetes. In one embodiment, thesecond agent is linsulin or an insulin analog.

In one aspect, the invention provides a method for delaying the onset ofsevere hypoglycemia in a subject, the method comprising administering acompound of the present invention or pharmaceutically acceptable saltthereof, to the subject. In one embodiment, the subject has diabetes. Inone embodiment, the method involves coadministration of a compound ofthe present invention or pharmaceutically acceptable salt thereof with asecond agent useful in the treatment of diabetes. In one embodiment, thesecond agent is linsulin or an insulin analog.

In one aspect, the invention provides a method for restoring a glucagonresponse to low blood glucose level in a subject, the method comprisingadministering a compound of the present invention or pharmaceuticallyacceptable salt thereof, to the subject. In one embodiment, the subjecthas diabetes. In one embodiment, the method involves coadministration ofa compound of the present invention or pharmaceutically acceptable saltthereof with a second agent useful in the treatment of diabetes. In oneembodiment, the second agent is linsulin or an insulin analog.

In one aspect, the invention provides a method for facilitating anincrease in glucagon secretion in response to low blood glucose level ina subject, the method comprising administering a compound of the presentinvention or pharmaceutically acceptable salt thereof, to the subject.In one embodiment, the subject has diabetes. In one embodiment, themethod involves coadministration of a compound of the present inventionor pharmaceutically acceptable salt thereof with a second agent usefulin the treatment of diabetes. In one embodiment, the second agent islinsulin or an insulin analog.

In one aspect, the invention provides a method for de-repressingglucagon secretion under conditions of low blood glucose level in asubject, the method comprising administering a compound of the presentinvention or pharmaceutically acceptable salt thereof, to the subject.In one embodiment, the subject has diabetes. In one embodiment, themethod involves coadministration of a compound of the present inventionor pharmaceutically acceptable salt thereof with a second agent usefulin the treatment of diabetes. In one embodiment, the second agent islinsulin or an insulin analog.

In one aspect, the invention provides a method for facilitating anincrease in glucagon levels in the portal vein in response to low bloodglucose level in a subject, the method comprising administering acompound of the present invention or pharmaceutically acceptable saltthereof, to the subject. In one embodiment, the subject has diabetes. Inone embodiment, the method involves coadministration of a compound ofthe present invention or pharmaceutically acceptable salt thereof with asecond agent useful in the treatment of diabetes. In one embodiment, thesecond agent is linsulin or an insulin analog.

Low blood glucose level means a blood glucose level below that ofeuglycemia. In one embodiment, the low blood glucose level is betweenthat of euglycemia and hypoglycemia. In one embodiment, the low bloodglucose level is indicative of hypoglycemia. In one embodiment, the lowblood glucose level is indicative of severe hypoglycemia. In oneembodiment, the low blood glucose level is below 4 mM. In oneembodiment, the low blood glucose level is 3.9 mM or below. In oneembodiment, the low blood glucose level is 2.9 mM or below. In oneembodiment, the low blood glucose level is 1.9 mM or below.

In one aspect, the invention provides a method for delaying ahypoglycemic event in a subject, the method comprising administering acompound of the present invention or pharmaceutically acceptable saltthereof, to the subject. In one embodiment, the subject has diabetes. Inone embodiment, the method involves coadministration of a compound ofthe present invention or pharmaceutically acceptable salt thereof with asecond agent useful in the treatment of diabetes. In one embodiment, thesecond agent is linsulin or an insulin analog.

Administration of a compound as disclosed herein “in combination with”one or more further agents, or “coadministration” with one or morefurther agents, for example insulin, is intended to include simultaneous(concurrent) administration and consecutive administration. Simutaneousadministration may involve coformulation of a compound disclosed hereinwith one or more further agents, for example, insulin, or may involveseparate formulations. Consecutive administration is intended toencompass various orders of administration of the agents to a subject,with administration of the agent being separated by a time period thatmay be short (for example, on the order of minutes) or extended (forexample in the order of hours, days or weeks).

An “effective amount” of a pharmaceutical composition as describedherein includes a therapeutically effective amount or a prophylacticallyeffective amount. A “therapeutically effective amount” refers to anamount effective, at dosages and for periods of time necessary, toachieve the desired therapeutic result, such as increasing blood glucoseto a desired level, decreasing the duration of hypoglycemia, decreasingthe duration of severe hypoglycemia, decreasing the severity ofhypoglycemia, increasing life span or increasing life expectancy. Atherapeutically effective amount of a compound may vary according tofactors such as the disease state, age, sex, and weight of the subject,and the ability of the compound to elicit a desired response in thesubject. Dosage regimens may be adjusted to provide the optimumtherapeutic response. A therapeutically effective amount is also one inwhich any toxic or detrimental effects of the compound are outweighed bythe therapeutically beneficial effects. A “prophylactically effectiveamount” refers to an amount effective, at dosages and for periods oftime necessary, to achieve the desired prophylactic result, such asmaintaining blood glucose levels in a desired range, preventinghypoglycemia, preventing severe hypoglycemia, decreasing the duration ofhypoglycemia, decreasing the duration of severe hypoglycemia, decreasingthe severity of hypoglycemia, decreasing the probability ofhypoglycemia, decreasing the probability of severe hypoglycemia,increasing life span, increasing life expectancy or prevention of theprogression of the condition. Typically, a prophylactic dose is used insubjects prior to or at an earlier stage of disease or condition. Insome instances a prophylactically effective amount may be less than atherapeutically effective amount. In the present context, a compound ofthe invention may be administered prophylactically in order to preventor reduce the hypoglycemia or severe hypoglycemia that would otherwiseoccur in the absence of administration of the subject compound. Forexample, compound of the invention may be administered prophylacticallyto a diabetic subject receiving insulin in order to prevent or reducethe hypoglycemia or severe hypoglycemia that would otherwise occur inthe subject in the absence of such compound.

It is to be noted that dosage values may vary with the severity of thecondition to be alleviated. For any particular subject, specific dosageregimens may be adjusted over time according to the individual need andthe professional judgment of the person administering or supervising theadministration of the compositions. Dosage ranges set forth herein areexemplary only and do not limit the dosage ranges that may be selectedby medical practitioners. The amount of active compound(s) in thecomposition may vary according to factors such as the disease state,age, sex, and weight of the subject. Dosage regimens may be adjusted toprovide the optimum therapeutic response. For example, a single bolusmay be administered, several divided doses may be administered over timeor the dose may be proportionally reduced or increased as indicated bythe exigencies of the therapeutic situation. It may be advantageous toformulate parenteral compositions in dosage unit form for ease ofadministration and uniformity of dosage.

In some embodiments, compounds and all different forms thereof asdescribed herein may be used, for example, and without limitation, incombination with other treatment methods.

Compounds as described herein may be administered to a subject. In someembodiments, the subject may be a mammal. In other embodiments, thesubject may be a human, non-human primate, rat, mouse, cow, horse, pig,sheep, goat, dog, cat, etc. In some embodiments, the subject hasdiabetes. In other embodiments, the subject has type 1 or type 2diabetes. In other embodiments, the subject has type 1 diabetes. Inother embodiments, the subject has type 2 diabetes.

It will be understood by the artisan of reasonable skill in the art thatthe cyclic peptides of the invention exhibiting affinity for SSTR2 orSSTR2 antagonistic activity may be used in place of known SSTR2 ligandsand antagonists in certain applications and methods. For example, see WO2009/129311, which is expressly incorporated herein in its entirety byreference.

A variety of additions may be made, for example, to the N-terminal aminoacid of a cyclic peptide disclosed herein, in the form of a complexingor conjugating agent (Z) that can then be used to join a desired moietyto the peptide or to provide labeling. Such a moiety Z generally can beselected from the group consisting of DOTA- and DTPA-based chelators,NOTA-based chelators, carbonyl compounds, 2-hydrazino nicotinamide(HYNIC), N₄-chelators, desferrioxamin, and N_(x)S_(y)-chelators, alloptionally complexed with a radioisotope, Tyrosine (Tyr) forhalogenation, a fluorescent dye or biotin. Cpa can also serve as aprecursor for tritiation. A chelator, such as, for example, DTPA, DOTA,HYNIC and P₂S2-COOH can be attached. Chelators include, for example,p-NH₂—Bz-DOTA(2-p-aminobenzyl-1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraaceticacid), and DOTA-p-NH₂-anilide[1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acidmono(p-aminoanilide)]. Alternatively, a chelating agent can becovalently linked to the N-terminus via a suitable linker if desired.Suitable linkers include, for example, tyrosine, lysine, diaminobutyricacid, diaminopropionic acid, polyethylene glycol, fatty acids and theirderivatives, s-alanine, 5-amino valeric acid, sarcosine, and gluceronicacid. Where Tyr appears at the N-terminus, it can be radioiodinated orotherwise labeled. Acyl groups having not more than about 20 amino acidscan also be present at the N-terminus, as the N-terminal residue canalso be acylated, if desired, with a bulky moiety without loss ofselectivity.

The invention is also directed to, for example, a method ofintraoperatively detecting malignant tumors in the body of a human beingin tissues that in healthy condition do not contain substantialquantities of SSTR2. The method includes, for example (i) administeringto such being a composition comprising, in a quantity sufficient fordetection by a gamma detecting probe, cyclic peptide disclosed herein,wherein the peptide is labeled, e.g., radioactively with ^(99m)Tc,¹⁶¹Tb₅ ⁹⁰Y, ¹⁷⁷Lu, ¹²³I or ¹²⁵I, and (ii) after allowing the activesubstance to be bound and taken up in the tumors and after bloodclearance of radioactivity, and subjecting such being to aradiodetection technique in the relevant area of the body by using agamma-detecting probe.

The use of external imaging by radioactive scanning or by magneticresonance allows semiquantitative detection within the body.

The compositions of the present invention are also useful inscintigraphy to determine the distribution of cells and tissuesexpressing SSTR2 throughout the body.

The compositions of the present invention are also useful as therapeuticagents comprising radioisotopes that are targeted to tumor cellsexpressing SSTR2. In one embodiment, radiolabeled compositions of theinvention are useful for the therapeutic treatment of malignant tumorsin the body of a human being in tissues that, in healthy condition, donot contain substantial quantities of SSTR2. Radiolabeled compositionscan be administered in a composition that includes a quantity effectivefor scintigraphy or for combating or controlling tumors. Theradiolabeled peptides can be labeled, for example, with ¹⁸⁶Re, ¹⁸⁸Re,¹¹¹In, ^(113m)In, ⁷¹As, ⁹⁰Y, ⁶⁷Cu, ^(99m)Tc, ¹⁶⁹Er, ¹²¹Sn, ¹²⁷Te, ¹⁴²Pr,¹⁴³Pr, ⁶⁶Ga, ⁶⁷Ga, ⁶⁸Ga, ⁷²Ga, ¹²⁷Te, ¹⁹⁵Pt, ²¹¹At, ¹⁹⁸Au, ¹⁹⁹Au, ¹⁶¹Tb,¹⁰⁹Pd, ¹⁶⁵Dy, ¹⁴⁹Pm, ¹⁵¹Pm, ¹⁵³Sm, ¹⁵⁷Gd, ¹⁵⁹Gd, ¹⁶⁶Ho, ¹⁷²Tm, ¹⁶⁹Yb,¹⁷⁵Yb, ¹⁷⁷Lu, ¹⁰⁵Rh, ¹¹⁴Ag, ¹²⁴I or ¹³¹I.

The present disclosure provides methods for assessing the affinity ofcompositions toward SSTR. The present disclosure provides methods forassessing the antagonistic activity of compositions toward SSTR. In oneembodiment, there are provided methods for assessing the affinity and/orantagonistic activity of compositions toward SSTR2. In one embodiment,there are provided methods for assessing the affinity and/orantagonistic activity of compositions toward SSTR5. In one embodiment,there are provided methods for determining the selectivity of acomposition for SSTR2 and/or SSTR5 as compared to other SSTRs.

In one embodiment, labeled compositions of the invention are useful indrug-screening assays to screen for new effective peptide andnon-peptide agents that bind with high affinity to SSTR2 and are highlyeffective antagonists. Using a ligand as described herein that isselective for the receptor SSTR2, one can obtain a baseline activity fora recombinantly-produced receptor. A competitive binding assay for SSTR2with the labeled ligand and the candidate can then be carried out todetermine the relative binding affinity. Alternatively, prospectivecandidates for inhibitors or modifiers, e.g., antagonists of thereceptor function, can be directly incorporated into an assay mixture todetermine the effect of such candidate on the receptor. By comparing theextent of receptor activity in the presence or absence of the candidatesubstance, one can then obtain information regarding the effect of thecandidate substance on the normal function of the receptor and thusdetermine its function as either an agonist or an antagonist compared toa known SSTR2-selective analog.

The compositions of the present invention are also useful forselectively blocking certain of the pharmacological effects that aremediated by particular SSTRs. In one embodiment, compositions of theinvention are useful for selectively blocking certain of thepharmacological effects that are mediated by SSTR2. In one embodiment,compositions of the invention are useful for selectively blockingcertain of the pharmacological effects that are mediated by SSTR2 and/orSSTR5. The many effects of SSTRs are known in the art. In oneembodiment, non-radiolabeled compositions of the invention may be usedto treat diseases of an organ or tissue known to express SSTR2,including but not limited to, lung, gastrointestinal tract and kidneys.

In one embodiment, compositions of the invention can be complexed with aradioactive nuclide for the purpose of carrying that agent to a tumor orother tissue for which apoptosis is desired. For example, suitablechelating agents, such as DOTA or DTPA or others, can be used to complexthe composition with a highly radioactive metal as indicatedhereinbefore. Some examples of suitable chelating groups for chelating aradioactive metal atom are tetradentate chelating agents or groupsderived from ethylene diamine tetra-acetic acid (EDTA), diethylenetriamine penta-acetic acid (DTPA), cyclohexyl 1,2-diamine tetra-aceticacid (CDTA),ethyleneglycol-0,0′-bis(2-aminoethyl)-N,N,N′,N′-tetra-acetic acid(EGTA), N,N-bis(hydroxybenzyl)-ethylenediamine-N,N′-diacetic acid(HBED), Methylene tetramine hexa-acetic acid (TTHA),1,4,7,10-tetraazacyclododecane-N,N′,N″,N′″-tetra-acetic acid (DOTA),hydroxyethyldiamine triacetic acid (HEDTA),1,4,8,11-tetraazacyclo-tetradecane-N,N′,N″,N′″-tetra-acetic acid (TETA),substituted DTPA, substituted EDTA. Other chelators, as well asradioactive agents, are disclosed in WO 95/22341 and WO 04/082722 and inU.S. Patent Publications 2004/0242842 and 2005/0070470, the entirecontents of which are incorporated herein by reference. Chelators can bederived from, for example, EDTA and DOTA. Some suitable salts are^(m)In-oxinte, ^(99m)Tc-tartrate, which can generally be formed in asimple manner under conditions that are not detrimental to the peptideantagonist.

The cyclic peptides of the present invention can be synthesized bymethods known to those of ordinary skill in the art, including classicalsolution synthesis and solid-phase techniques. For example, the cyclicpeptides may be synthesized using solid-phase techniques such as on amethylbenzhydrylamine (MBHA) resin or a BHA resin, as is known in thisart. Peptides having a free carboxyl C-terminus can be synthesized astaught in U.S. Pat. No. 7,019,109, the contents of which are hereinincorporated by reference in their entirety. Peptides having an amidatedC-terminus can be synthesized as taught in U.S. Pat. No. 5,874,227, thecontents of which are herein incorporated by reference in theirentirety. Solid-phase synthesis is conducted in a manner that adds aminoacids in the chain beginning at the C-terminus in a stepwise manner.Side-chain protecting groups, which are known in the art, are includedas a part of any amino acid that has a particularly reactive side chain,and optionally can be used in the case of others such as Trp, where suchamino acids are coupled onto the chain being built upon the resin. Suchsynthesis provides a fully protected intermediate peptidoresin.Protecting groups are generally split off and the peptide is cleavedfrom the resin support before cyclizing the peptide. For example, in thecase of a disulfide linkage, protecting groups are generally split offand the peptide is cleaved from the resin support before oxidizing tocreate a disulfide bond between the Cys side chains.

Various alternative embodiments and examples are described herein. Theseembodiments and examples are illustrative and should not be construed aslimiting the scope of the invention. All references and citations areexpressly incorporated herein in their entirety by reference.

EXAMPLES General Methodologies Chemical Synthesis

Compounds of the present invention were prepared in an iterativefashion. The linear 8-mer peptide intermediates were prepared by solidphase peptide synthesis (SPPS) using Fmoc protected amino acids and RinkAmide MBHA resin according to routine solid phase peptide synthesis(see, for example, Beilstien J. Org. Chem. 2014, 10, 1197-1212).Combinations of natural and non-natural Fmoc protected amino acids wereprepared or obtained from commercial sources.

After final Fmoc deprotection and acid induced cleavage of the peptideintermediates from the resin (with concurrent in situ deprotection ofacid labile protecting groups), the resulting linear 8-mer peptideintermediates were further cyclized using cysteine-cysteine dithiolcoupling conditions, including iodine (I₂) oxidation. Final purificationby preparative HPLC provided the desired cyclic compounds.

Alternatively, it was possible to cyclize the peptides via thecysteine-cysteine dithiol bond by selectively deprotecting the cysteineresidues while the peptide remained bound to the resin.

Peptides that were cyclized via a cysteine-cysteine disulfide isosterein place of the disulfide employed conditions specific to thatparticular linker.

Abbreviations referred to in the chemical synthesis methodologies andexamples represent the following: Ac=acetyl; ACN=acetonitrile;All=allyl; Aph=4-aminophenylalanine; Arg=arginine; Asn=aspargine;Asp=aspartic acid; Boc=tert-butyloxycarbonyl; Cit=citrulline;Cpa=4-chlorophenylalanine; Cys=cysteine; Dap=2,3-diaminoproprionic acid;DCE=1,2-dichloroethane; DCM=dichloromethane;DIC=N,N′-diisopropylcarbodiimide; DIPEA=diisopropylethylamine;DMF=N,N-dimethylformamide; EDT=1,2-ethanedithiol;Fmoc=9-fluorenylmethoxycarbonyl; Gln=glutamine; Glu=glutamic acid;Gly=glycine;HATU=1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium3-oxid hexafluorophosphate;HBTU=2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluroniumhexafluorophosphate; HOAt=1-hydroxy-7-azabenzotriazole;HoCit=homocitrulline; HPLC=high performance liquid chromatography;Lys=Lysine; MBHA=4-methylbenzhydrylamine; Mtt=4-methyltrityl;NMM=N-methylmorpholine; OxymaPure=ethyl (hydroxyimino)cyanoacetate;Pbf=2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl;Phe=phenylalanine; Pro=proline; Ser=serine; SPPS=solid phase peptidesynthesis; Su=succinate; tBu=tert-butyl; TEA=triethylamine;TFA=trifluoroacetic acid; THE=tetrahydrofuran; Thr=threonine;TIPS=triisopropylsilane; Tle=tert-leucine=tert-butylglycine;Trt=trityl=triphenylmethyl; Tyr=tyrosine; Val=valine;

Example 1:H-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-n-pentylamino)-Lys-Thr-Cys]-D-Tyr-NH₂(Compound 12) Preparation of the Peptidyl-MBHA Resin

Rink Amide MBHA resin (0.1 mmol) was swelled in DMF (10 mL) for 2.0hours. The suspension was filtered. 20% piperidine in DMF (10 mL) wasadded into the resin. The suspension was kept at room temperature for0.5 h while a stream of nitrogen was bubbled through it. Then thesuspension was filtered. The resin was washed with DMF (6×10 mL).Fmoc-D-Tyr(tBu)-OH (0.138 g, 0.3 mmol), HBTU (0.108 g, 0.285 mmol),N-methylmorpholine (0.067 mL, 0.6 mmol) and DMF (5 mL) were added intothe resin. The suspension was kept at room temperature for 2.0 h while astream of nitrogen was bubbled through it. Once a ninhydrin testindicated the completion of the coupling, the peptidyl resin was washedwith DMF (3×10 mL) and dried.

Peptide Synthesis

Fmoc-deprotection was performed using 20% piperidine/DMF, followed byresin washing. Repeat coupling and deprotection cycles with theappropriately protected Fmoc-amino acids followed to provide the fullpeptide sequence. The peptidyl-MBHA resin was washed with DMF (3×10 mL),MeOH (2×10 mL), DCM (2×10 mL) and MeOH (2×10 mL), then it was driedunder vacuum overnight to provide the peptidyl-MBHA resin.

Cleavage of the Peptide Intermediate from the RINK Resin

3 mL of TFA:thioanisole:phenol:EDT:H₂O (87.5:5:2.5:2.5:2.5) was added tothe peptidyl-MBHA resin in a glass vessel. The mixture was stirred for 3hours. The suspension was filtered and the filtrate was collected andfurther treated with cold diethyl ether (30 mL). The resultingprecipitate was centrifuged. The diethyl ether layer was removed and thecake was washed with cold diethyl ether (2×30 mL), and dried undervacuum to provide 50 mg of crude peptide intermediate 12-vi.

Cyclization of the Linear 8-Mer Peptide Intermediates

50 mg of crude peptide intermediate 12-vi was oxidized by I₂ in anappropriate solvent, concentrated under reduced pressure and the residuewas purified by preparative HPLC to provide 9.4 mg of Compound 12, as awhite solid (95.1% purity by HPLC, TFA salt).

Example 2:H-Cpa-cyclo[D-Cys-Tyr-D-Lys(N^(ε)-nicotinoyl)-Lys(N^(ε)-Me)-Thr-Cys]-D-Tyr-NH₂(Compound 30) Preparation of the Peptidyl-MBHA Resin

Rink Amide MBHA resin (0.1 mmol) was swelled in DMF (10 mL) for 2.0hours. The suspension was filtered. 20% piperidine in DMF (10 mL) wasadded into the resin. The suspension was shaken gently at roomtemperature for 0.5 h. Then the suspension was filtered. The resin waswashed with DMF (6×10 mL). Fmoc-D-Tyr(tBu)-OH (0.138 g, 0.3 mmol), HBTU(0.108 g, 0.285 mmol), N-methylmorpholine (0.067 mL, 0.6 mmol) and DMF(5 mL) were added into the resin. The suspension was kept at roomtemperature for 2.0 h while being shaken gently. Once a ninhydrin testindicated the completion of the coupling, the peptidyl resin was washedwith DMF (6×10 mL).

Peptide Synthesis

Fmoc-deprotection was performed using 20% piperidine/DMF, followed byresin washing. Repeat coupling and deprotection cycles with theappropriately protected Fmoc-amino acids followed to provide the fullpeptide sequence. Cysteines were added to the peptide sequence using DIC(3.0 eq) and OxymaPure (3.0 eq) in place of HBTU/NMM. The final aminoacid used in the peptide synthesis could be either an Fmoc- or Boc-aminoacid; Fmoc amino acids require a final piperidine deprotection whereasBoc amino acids are deprotected during cleavage of the peptide from theresin. The peptidyl-MBHA resin was washed with DMF (3×10 mL), MeOH (2×10mL), DCM (2×10 mL) and MeOH (2×10 mL), then it was dried under vacuumovernight to provide the peptidyl-MBHA resin.

Cleavage of the Peptide Intermediate from the Rink Resin

3 mL of TFA:thioanisole:phenol:EDT:H₂O (87.5:5:2.5:2.5:2.5) was added tothe peptidyl-MBHA resin in a glass vessel. The mixture was stirred for 3hours. The suspension was filtered and the filtrate was collected andfurther treated with cold diethyl ether (30 mL). The resultingprecipitate was centrifuged. The diethyl ether layer was removed and thecake was washed with cold diethyl ether (2×30 mL), and dried undervacuum to provide 50 mg of crude peptide intermediate 12-vi.

Cyclization of the Linear 8-Mer Peptide Intermediate

50 mg of crude peptide intermediate 12-vi was oxidized by I₂ in anappropriate solvent, concentrated under reduced pressure and the residuewas purified by preparative HPLC (reverse phase, ACN/water+0.1% TFAmodifier) to provide 9.4 mg of compound 12, as a white solid (95.1%purity by HPLC).

General Cleavage and Cyclization Methods

General Method A: Alternative Method for the Cleavage of a CyclicPeptide from the Rink Resin

3 mL of TFA:TIPS:H₂O (96.5:2.5:1) was added to the peptidyl-MBHA resin.The mixture was agitated for 3 h, drained and rinsed with DCM (3×5 mL)and MeOH (3×5 mL). The combined filtrate was concentrated in vacuo to aminimal amount, treated with cold diethyl ether (30 mL) and theresulting precipitate was centrifuged. The diethyl ether layer wasdecanted and the cake was washed with cold diethyl ether (2×30 mL) toprovide an off-white solid. The crude material was purified bypreparative HPLC (reverse phase, ACN/water+0.1% TFA modifier) to providethe cyclic peptide as a white solid.

General Method B: On-Resin Cyclization of Peptides Containing aCysteine-Cysteine Disulfide Bridge

Some peptides described in this invention were prepared by forming thecysteine-cysteine disulfide bridge while the peptide was still bound tothe resin. The linear, resin-bound peptides were formed according toExample 2.

The peptidyl-MBHA resin was treated with TFA:TIPS:DCM (5:2:93, 0.025 M,3×10 min) and then rinsed with DCM (3×5 mL). The resin was suspended inDMF:MeOH (9:1, 0.025M) and treated with I₂ (3 eq). After agitation for 2h, the mixture was drained and then rinsed with DMF (3×5 mL), MeOH (2×5mL), DCM (2×5 mL), and MeOH (2×5 mL) and then it was dried in vacuoovernight. The cyclization was deemed complete via an Ellman's test. Thecyclic peptide was cleaved from the resin using General Method A to givethe desired peptide.

General Method C: Preparation of N-Terminal Acylated Peptides

Some peptides described in this invention are acylated on the N-terminalnitrogen (peptides 49-58). The linear, resin-bound peptides wereprepared according to Example 2, using an Fmoc-protected amino acid atthe N-terminus. Following removal of the N-terminal Fmoc, the acyl groupis added by HBTU mediated coupling of the corresponding carboxylic acidto the resin-bound peptide. Alternatively, activated acids such as acidchlorides and acid anhydrides could be used to attach the acyl group tothe N-terminus of the peptide. The final peptides were cyclized, cleavedfrom the resin and purified according to General Method B.

General Method D: Synthesis of Peptides Containing a Thiocarbamate—NH—(C═O)—S— Bridge (60-63)

The Dap-containing intermediate peptidyl-MBHA resin (60-ii to 63-i) wastreated with either 20% piperidine/DMF for 30 min and then rinsed withDMF (3×5 mL) and THE (3×5 mL) (Fmoc protected Dap) or TFA:TIPS:DCM(3:3:94, 0.05 M, 3×10 min) and then rinsed with THE (3×5 mL) (Mttprotected Dap). The resin was suspended in THE (0.025 M) andsuccessively treated with DIPEA (4 eq) and PhS(C═O)Cl (4 eq). Afteragitation for 2 h, the mixture was drained and then rinsed with THE (3×5mL), DCM (3×5 mL) and DMF (3×5 mL). The thiocarbamate formation wasdeemed complete via a Kaiser test. The resin was then suspended inPhSH:DIPEA:DMF (6:9:85, 0.02 M), agitated for 16-72 h, drained andrinsed with DMF (3×5 mL) and DCM (3×5 mL). The cyclic peptide wascleaved from the resin using General Method A to give peptides 60-63.

Note: Resin-bound peptide intermediate 60-ii was prepared usingBoc-Cpa-D-Dap(Fmoc)-OH (60-i) to form the N-terminal end of the peptide.The synthesis of this dipeptide is described below.

General Method E: Synthesis of Peptides Containing a Triazole Bridge(64-66)

The intermediate peptidyl-MBHA resin (64-i to 66-i) was treated with DMF(0.02M), DIPEA (10 eq.), 2,4-lutidine (10 eq.), sodium L-ascorbate (3eq.) and CuBr (1 eq., 0.014M in ACN). The mixture was purged with Ar for5 min and then agitated for 5 h. The resin was filtered and successivelywashed with DMF (3×10 mL), H₂O (2×10 mL), and MeOH (2×10 mL) and then itwas dried in vacuo overnight. The cyclic peptide was cleaved from theresin using General Method A to give the desired peptides 64-66.

Note: For compound 64-i, the N-terminal Fmoc protecting group wasremoved using standard Fmoc deprotection conditions before the cyclicpeptide was cleaved from the resin.

General Method F: Synthesis of Stapled Peptides (67-68, Alkene Bridge)

The intermediate peptidyl-MBHA (67-i to 68-i) resin was treated with DCM(0.03M) and Grubbs Catalyst™ 2nd Generation (0.25 eq., 0.04M in DCM).The mixture was purged with Ar for 10 min and then heated at 40° C. in asealed vessel for 3 d. The resin was filtered and successively washedwith DCM (3×10 mL), and MeOH (2×10 mL) and then it was dried in vacuoovernight. The cyclic peptide was cleaved from the resin using GeneralMethod A to give the desired peptides 67-68.

General Method G: Synthesis of Peptides Containing an Amide Bridge(69-71)

The intermediate peptidyl-MBHA (69-i-71-i) resin was treated withmorpholine (2 eq.) and DCM (0.03M). The resulting mixture was purgedwith Ar for 10 min. Pd(PPh₃)₄ (0.25 eq.) was added and the mixture wasagitated for 20 h. The resin was filtered and successively washed withDMF (3×10 mL) and DCM (2×10 mL). The Mtt protecting group wasselectively cleaved via treatment with TFA:TIPS:DCM (3:3:94, v/v/v, 3×10min). The resin was filtered and successively washed with DCM (3×10 mL)and DMF (2×10 mL). HBTU (3 eq.), NMM (3 eq.) and DMF (0.03M) were addedto the resin and the mixture was agitated for 24 h. The resin wasfiltered and successively washed with DMF (3×10 mL) and DCM (2×10 mL),and then it was dried in vacuo overnight. The cyclic peptide was cleavedfrom the resin using General Method A to give the desired peptides69-71.

General Method H: Counterion Exchange from Trifluoroacetate to Acetate.

The peptides in this invention were generally purified by preparativeHPLC, producing the peptides as TFA salts. Selected compounds wereconverted to acetic acid salts using the following anion exchangemethod. A column of strong anion exchange resin was prepared (AmberliteIRA-400 (Cl)) with an 80 fold excess of anion sites relative to thepeptide. The column was eluted with a 1M aqueous solution of sodiumacetate. The column was washed with deionized water to remove the excesssodium acetate. The peptide was dissolved in distilled water and appliedto the column. The column was eluted with distilled water and thefraction(s) containing the peptide were collected. The combinedfractions were lyophilized, obtaining the desired peptides as theacetate salts.

General Method I: Synthesis of N^(α)-Methylated Peptides

The synthesis of N^(α)-methylated peptides generally followed theprocedure described in Example 2, with some modifications. TheN^(a)-methyl groups were either introduced on-resin during the solidphase peptide synthesis according to Chatterjee et. al., NatureProtocols, Vol. 7, No. 3, 2012, p 432-444, or by purchasing commerciallyavailable N-methyl amino acid(s). Extending the resin-bound peptide bycoupling an Fmoc amino acid to an N-terminal methylated intermediaterequired the use of HATU (3 eq), HOAt (3 eq) and DIPEA (6 eq) in placeof HBTU/NMM. Completion of this coupling was monitored by the chloraniltest, and repeated when necessary. In examples where cysteine is coupledto an N-terminal methylated intermediate, OxymaPure was used as thecoupling reagent as described in Example 2. Completion was againmonitored by the chloranil test, and repeated where necessary.

General Method J: Preparation of N-Terminal Sulfonylated Peptides

The synthesis of N-terminal sulfonamide peptides generally followed theprocedure described in Example 2, with some modifications. Followingremoval of the N-terminal Fmoc from the linear, resin-bound peptides,the sulfonamide derivatives were made by treating the linear resin boundpeptide with the corresponding sulfonyl chloride (3 eq.) and DIPEA (6eq.) in DMF (0.02M). After agitation for 2 h, the mixture was drainedand rinsed with DMF (3×), MeOH (2×), DCM (2×), and MeOH (2×) and then itwas dried in vacuo overnight. The linear peptide was cleaved from theresin and cyclized as described in Example 2 to give the desiredpeptides 81-82.

Example 3:H-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-phenylureido)-Lys(N^(ε)-Me)-Thr-Cys]-D-Tyr-NH₂(Compound 25)

Compound 25 was prepared according to the procedure described in Example2, using the following amino acids: Fmoc-D-Tyr(tBu)-OH,Fmoc-Cys(Trt)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Lys(N^(ε)-Boc-N^(ε)-Me)-OH,15-ii, Fmoc-Tyr(tBu)-OH, Fmoc-D-Cys(Trt)-OH and Fmoc-Cpa-OH. Compound 25was a white solid, recovered as the 2-TFA salt in 10% yield.

Example 4:H-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-carbamoyl)-Lys(N^(ε)-diMe)-Thr-Cys]-D-Tyr-NH₂(Compound 32)

Compound 32 was prepared according to the procedure described in Example2, using the following amino acids: Fmoc-D-Tyr(tBu)-OH,Fmoc-Cys(Trt)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Lys(N^(ε)-diMe)-OH,Fmoc-D-Phe(4-carbamoyl)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-D-Cys(Trt)-OH andFmoc-Cpa-OH. Compound 32 was a white solid, recovered as the 2-TFA saltin 9% yield.

Example 5:H-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-carbamoyl)-Lys(N^(ε)-Me)-Thr-Cys]-D-Cpa-NH₂(Compound 46)

Compound 46 was prepared according to the procedure described in Example2, using the following amino acids: Fmoc-D-Cpa-OH, Fmoc-Cys(Trt)-OH,Fmoc-Thr(tBu)-OH, Fmoc-Lys(N^(ε)-Boc-N^(ε)-Me)-OH,Fmoc-D-Phe(4-carbamoyl)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-D-Cys(Trt)-OH andBoc-Cpa-OH. Compound 46 was a white solid, recovered as the 2-TFA saltin 29% yield.

Example 6:H-Cpa-cyclo[D-Cys-Cpa-D-Phe(4-carbamoyl)-Lys(N^(ε)-Me)-Thr-Cys]-D-Cpa-NH₂(Compound 47)

Compound 47 was prepared according to the procedure described in Example2, using the following amino acids: Fmoc-D-Cpa-OH, Fmoc-Cys(Trt)-OH,Fmoc-Thr(tBu)-OH, Fmoc-Lys(N^(ε)Boc-N^(ε)-Me)-OH,Fmoc-D-Phe(4-carbamoyl)-OH, Fmoc-Cpa-OH, Fmoc-D-Cys(Trt)-OH andBoc-Cpa-OH. Compound 47 was a white solid, recovered as the 2-TFA saltin 23% yield.

Example 7:H-Cpa-cyclo[D-Cys-Cpa-D-Phe(4-carbamoyl)-Lys(N^(ε)-Me)-Thr-Cys]-D-Tyr-NH₂(Compound 48)

Compound 48 was prepared according to the procedure described in Example2, using the following amino acids: Fmoc-D-Tyr(tBu)-OH,Fmoc-Cys(Trt)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Lys(N^(ε)-Boc-N^(ε)-Me)-OH,Fmoc-D-Phe(4-carbamoyl)-OH, Fmoc-Cpa-OH, Fmoc-D-Cys(Trt)-OH andBoc-Cpa-OH. Compound 48 was a white solid, recovered as the 2-TFA saltin 33% yield.

Example 8:H--Ala-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-carbamoyl)-Lys(N^(ε)-Me)-Thr-Cys]-D-Tyr-NH₂(Compound 49)

Compound 49 was prepared according to the procedures described inExample 2 and General Method C, using the following amino acids:Fmoc-D-Tyr(tBu)-OH, Fmoc-Cys(Trt)-OH, Fmoc-Thr(tBu)-OH,Fmoc-Lys(N^(ε)Boc-N^(ε)Me)-OH, Fmoc-D-Phe(4-carbamoyl)-OH,Fmoc-Tyr(tBu)-OH, Fmoc-D-Cys(Trt)-OH, Fmoc-Cpa-OH and Boc-β-Ala-OH.Compound 49 was a white solid, recovered as the 2-TFA salt in 6% yield.

Example 9:Ph(CO)NHCH₂(CO)-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-carbamoyl)-Lys(N^(ε)-Me)-Thr-Cys]-D-Tyr-NH₂(Compound 50)

Compound 50 was prepared according to the procedures described inExample 2 and General Method C, using the following amino acids:Fmoc-D-Tyr(tBu)-OH, Fmoc-Cys(Trt)-OH, Fmoc-Thr(tBu)-OH,Fmoc-Lys(N^(ε)Boc-N^(ε)Me)-OH, Fmoc-D-Phe(4-carbamoyl)-OH,Fmoc-Tyr(tBu)-OH, Fmoc-D-Cys(Trt)-OH, Fmoc-Cpa-OH and benzoylglycine.Compound 50 was a white solid, recovered as the TFA salt in 3% yield.

Example 10:PhSO₂CH₂(CO)-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-carbamoyl)-Lys(N^(ε)-Me)-Thr-Cys]-D-Tyr-NH₂(Compound 51)

Compound 51 was prepared according to the procedures described inExample 2 and General Method C, using the following amino acids:Fmoc-D-Tyr(tBu)-OH, Fmoc-Cys(Trt)-OH, Fmoc-Thr(tBu)-OH,Fmoc-Lys(N^(ε)Boc-N^(ε)Me)-OH, Fmoc-D-Phe(4-carbamoyl)-OH,Fmoc-Tyr(tBu)-OH, Fmoc-D-Cys(Trt)-OH, Fmoc-Cpa-OH and2-(phenylsulfonyl)acetic acid . Compound 51 was a white solid, recoveredas the TFA salt in 4% yield.

Example 11:t-BuCH₂(CO)-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-carbamoyl)-Lys(N^(ε)-Me)-Thr-Cys]-D-Tyr-NH₂(Compound 52)

Compound 52 was prepared according to the procedures described inExample 2 and General Method C, using the following amino acids:Fmoc-D-Tyr(tBu)-OH, Fmoc-Cys(Trt)-OH, Fmoc-Thr(tBu)-OH,Fmoc-Lys(N^(ε)-Boc-N^(ε)-Me)-OH, Fmoc-D-Phe(4-carbamoyl)-OH,Fmoc-Tyr(tBu)-OH, Fmoc-D-Cys(Trt)-OH, Fmoc-Cpa-OH and3,3-dimethylbutanoic acid. Compound 52 was a white solid, recovered asthe TFA salt in 10% yield.

Example 12:2-Pyridyl(CO)-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-carbamoyl)-Lys(N^(ε)-Me)-Thr-Cys]-D-Tyr-NH₂(Compound 53)

Compound 53 was prepared according to the procedures described inExample 2 and General Method C, using the following amino acids:Fmoc-D-Tyr(tBu)-OH, Fmoc-Cys(Trt)-OH, Fmoc-Thr(tBu)-OH,Fmoc-Lys(N^(ε)-Boc-N^(ε)-Me)-OH, Fmoc-D-Phe(4-carbamoyl)-OH,Fmoc-Tyr(tBu)-OH, Fmoc-D-Cys(Trt)-OH, Fmoc-Cpa-OH and picolinic acid.Compound 53 was a white solid, recovered as the TFA salt in 8% yield.

Example 13:H₂N(CO)(CH₂)₂(CO)-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-carbamoyl)-Lys(N^(ε)-Me)-Thr-Cys]-D-Tyr-NH₂(Compound 54)

Compound 54 was prepared according to the procedures described inExample 2 and General Method C, using the following amino acids:Fmoc-D-Tyr(tBu)-OH, Fmoc-Cys(Trt)-OH, Fmoc-Thr(tBu)-OH,Fmoc-Lys(N^(ε)Boc-N^(ε)Me)-OH, Fmoc-D-Phe(4-carbamoyl)-OH,Fmoc-Tyr(tBu)-OH, Fmoc-D-Cys(Trt)-OH, Fmoc-Cpa-OH and succinamic acid.Compound 54 was a white solid, recovered as the TFA salt in 5% yield.

Example 14:Ac-Gly-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-carbamoyl)-Lys(N^(ε)-Me)-Thr-Cys]-D-Tyr-NH₂(Compound 55)

Compound 55 was prepared according to the procedures described inExample 2 and General Method C, using the following amino acids:Fmoc-D-Tyr(tBu)-OH, Fmoc-Cys(Trt)-OH, Fmoc-Thr(tBu)-OH,Fmoc-Lys(N^(ε)Boc-N^(ε)Me)-OH, Fmoc-D-Phe(4-carbamoyl)-OH,Fmoc-Tyr(tBu)-OH, Fmoc-D-Cys(Trt)-OH, Fmoc-Cpa-OH and Ac-Gly-OH.Compound 55 was a white solid, recovered as the TFA salt in 4% yield.

Example 15:CH₃(CH₂)₄(CO)-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-carbamoyl)-Lys(N^(ε)-Me)-Thr-Cys]-D-Tyr-NH₂(Compound 56)

Compound 56 was prepared according to the procedures described inExample 2 and General Method C, using the following amino acids:Fmoc-D-Tyr(tBu)-OH, Fmoc-Cys(Trt)-OH, Fmoc-Thr(tBu)-OH,Fmoc-Lys(N^(ε)Boc-N^(ε)Me)-OH, Fmoc-D-Phe(4-carbamoyl)-OH,Fmoc-Tyr(tBu)-OH, Fmoc-D-Cys(Trt)-OH, Fmoc-Cpa-OH and hexanoic acid.Compound 56 was a white solid, recovered as the TFA salt in 8% yield.

Example 16:(Furan-2-carboxy)-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-carbamoyl)-Lys(N^(ε)-Me)-Thr-Cys]-D-Tyr-NH₂(Compound 57)

Compound 57 was prepared according to the procedures described inExample 2 and General Method C, using the following amino acids:Fmoc-D-Tyr(tBu)-OH, Fmoc-Cys(Trt)-OH, Fmoc-Thr(tBu)-OH,Fmoc-Lys(N^(ε)-Boc-N^(ε)-Me)-OH, Fmoc-D-Phe(4-carbamoyl)-OH,Fmoc-Tyr(tBu)-OH, Fmoc-D-Cys(Trt)-OH, Fmoc-Cpa-OH and 2-furoic acid.Compound 57 was a white solid, recovered as the TFA salt in 8% yield.

Example 17:CH₃O₂C(CH₂)₂(CO)-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-carbamoyl)-Lys(N^(ε)-Me)-Thr-Cys]-D-Tyr-NH₂(Compound 58)

Compound 58 was prepared according to the procedures described inExample 2 and General Method C, using the following amino acids:Fmoc-D-Tyr(tBu)-OH, Fmoc-Cys(Trt)-OH, Fmoc-Thr(tBu)-OH,Fmoc-Lys(N^(ε)-Boc-N^(ε)-Me)-OH, Fmoc-D-Phe(4-carbamoyl)-OH,Fmoc-Tyr(tBu)-OH, Fmoc-D-Cys(Trt)-OH, Fmoc-Cpa-OH and succinicanhydride. Compound 58 was a white solid, recovered as the TFA salt in9% yield.

Example 18:H—(N-Me)Cpa-cyclo[D-Cys-Tyr-D-Phe(4-carbamoyl)-Lys-Thr-Cys]-D-Tyr-NH₂(Compound 77)

Compound 77 was prepared according to the procedures described inExample 2 and General Method I, using the following amino acids:Fmoc-D-Tyr(tBu)-OH, Fmoc-Cys(Trt)-OH, Fmoc-Thr(tBu)-OH,Fmoc-Lys(Boc)-OH, Fmoc-D-Phe(4-carbamoyl)-OH, Fmoc-Tyr(tBu)-OH,Fmoc-D-Cys(Trt)-OH and Boc-(N-Me)Cpa-OH. Compound 77 was a white solid,recovered as the 2-TFA salt in 10% yield.

Example 19: H-Cpa-cyclo[D-Cys-Tyr-D-Cit-Lys-Thr-Cys]-D-Tyr-NH₂ (Compound1)

Compound 1 was prepared according to the procedure described in Example2, using the following amino acids: Fmoc-D-Tyr(tBu)-OH,Fmoc-Cys(Trt)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Lys(Boc)-OH, Fmoc-D-Cit-OH,Fmoc-Tyr(tBu)-OH, Fmoc-D-Cys(Trt)-OH and Boc-Cpa-OH. Compound 1 was awhite solid, recovered as the 2-TFA salt. Compound 1 was then subjectedto General Method H where the final peptide was a white solid, recoveredas the bis acetate salt in 32% overall yield.

Example 20:H-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-carbamoyl)-Lys-Thr-Cys]-D-Tyr-NH₂(Compound 4)

Compound 4 was prepared according to the procedure described in Example2, using the following amino acids: Fmoc-D-Tyr(tBu)-OH,Fmoc-Cys(Trt)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Lys(Boc)-OH,Fmoc-D-Phe(4-carbamoyl)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-D-Cys(Trt)-OH andBoc-Cpa-OH. Compound 4 was a white solid, recovered as the 2-TFA salt.Compound 4 was then subjected to General Method H where the finalpeptide was a white solid, recovered as the bis acetate salt in 33%overall yield.

Example 21:H-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-phenylureido)-Lys-Thr-Cys]-D-Tyr-NH₂(Compound 15)

Compound 15 was prepared according to the procedure described in Example2, using the following amino acids: Fmoc-D-Tyr(tBu)-OH,Fmoc-Cys(Trt)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Lys(Boc)-OH, 15-ii,Fmoc-Tyr(tBu)-OH, Fmoc-D-Cys(Trt)-OH and Boc-Cpa-OH. Compound 15 was awhite solid, recovered as the 2-TFA salt. Compound 15 was then subjectedto General Method H where the final peptide was a white solid, recoveredas the bis acetate salt in 30% overall yield.

Example 22:H-Cpa-cyclo[D-Cys-Tyr-D-Phe(4-carbamoyl)-Lys(N^(ε)-Me)-Thr-Cys]-D-Tyr-NH₂(Compound 24)

Compound 24 was prepared according to the procedure described in Example2, using the following amino acids: Fmoc-D-Tyr(tBu)-OH,Fmoc-Cys(Trt)-OH, Fmoc-Thr(tBu)-OH, Fmoc-Lys(N^(ε)-Boc-N^(ε)-Me)-OH,Fmoc-D-Phe(4-carbamoyl)-OH, Fmoc-Tyr(tBu)-OH, Fmoc-D-Cys(Trt)-OH andBoc-Cpa-OH. Compound 24 was a white solid, recovered as the 2-TFA salt.Compound 24 was then subjected to General Method H where the finalpeptide was a white solid, recovered as the bis acetate salt in 40%overall yield.

Synthesis of Non-Natural Amino Acid Intermediates

The following methods describe general methods for the preparation ofnon-natural amino acid intermediates used in the preparation ofcompounds of the instant invention.

Synthesis of Intermediate 11-iii

4-nitro-D-phenylalanine monohydrate (20.01 g, 87.7 mmol, 1.0 eq) wassuspended in MeOH (440 mL, 0.2 M) and cooled to 0° C. Thionyl chloride(12.7 mL, 175 mmol, 2.0 eq) was added dropwise to the stirring solution,and the reaction was warmed to room temperature over 30 minutes and thenheated to reflux for 24 h. After that time the reaction was cooled andthe solvent was evaporated. The residue was taken up in EtOAc (750 mL)and saturated aqueous NaHCO₃ (1 L). The layers were separated and theorganic layer was extracted with EtOAc (2×250 mL). The organic layerswere combined, washed with brine, dried over Na₂SO₄, filtered andconcentrated to give 4-nitro-D-phenylalanine methyl ester (11-i) as anorange oil (17.30 g, 77.2 mmol, 88%) that was used without furtherpurification.

4-nitro-D-phenylalanine methyl ester (11-i, 17.30 g, 77.2 mmol, 1.0 eq)was dissolved in acetonitrile/water (2:1, 510 mL, 0.15 M) and treatedwith Et₃N (22.6 mL, 162 mmol, 2.1 eq) and Boc₂O (21.9 g, 100 mmol, 1.3eq). After stirring at room temperature for 18 h, the solvent wasevaporated and the residue was taken up in EtOAc (750 mL). This organicsolution was washed with saturated aqueous NH₄Cl (250 mL), saturatedaqueous NaHCO₃ (250 mL) and brine (250 mL), dried over Na₂SO₄, filteredand concentrated to afford Boc-4-nitro-D-phenylalanine methyl ester(11-ii, 22.57 g, 69.6 mmol, 90%) as a pale yellow solid that was usedwithout further purification.

Boc-4-nitro-D-phenylalanine methyl ester (11-ii, 22.57 g, 69.6 mmol) wasdissolved in MeOH/H₂O (10:1, 660 mL, 0.1 M). While vigorously stirring,Zn dust (45.5 g, 696 mmol, 10 eq) and NH₄Cl (55.8 g, 1043 mmol, 15 eq)were added and the mixture was heated to reflux for 90 min. The reactionwas cooled to room temperature and the solids were removed by filtrationthrough a pad of Celite. The filter cake was washed with MeOH. Thefiltrate was concentrated and the residue was dissolved in EtOAc (750mL). This organic solution was washed with water (250 mL), saturatedaqueous NH₄Cl (250 mL) and brine (250 mL), dried over Na₂SO₄, filteredand concentrated to afford Boc-4-amino-D-phenylalanine methyl ester(11-iii, 17.93 g, 60.9 mmol, 88%) as an orange oil. ¹H NMR (400 MHz,d₄-MeOH) δ=6.93 (d, J=8.3 Hz, 2H), 6.66 (d, J=8.3 Hz, 2H), 4.27 (dd,J=8.4, 5.8 Hz, 1H), 3.67 (s, 3H), 2.94 (dd, J=13.8, 5.8 Hz, 1H), 2.79(dd, J=13.9, 8.4 Hz, 1H), 1.39 (s, 9H).

Synthesis of Intermediate 11-iv

Boc-4-amino-D-phenylalanine methyl ester (11-iii, 1.39 g, 4.72 mmol, 1.0eq) was dissolved in DMF (45 mL, 0.1 M) and treated with K₂CO₃ (2.62 g,18.9 mmol, 4.0 eq) and the mixture was stirred for 15 min at roomtemperature. 4-(2-bromoethyl)morpholine hydrobromide (1.30 g, 4.73 mmol,1.0 eq) was added and the mixture was stirred at room temperature for 48h. Solids were removed by filtration. The filtrate was diluted withwater (450 mL) and it was extracted with EtOAc (3×). The organic layerswere combined, dried over Na₂SO₄, filtered and concentrated to afford11-iv as an orange oil (1.52 g, 79%) which was used in the next stepwithout further purification. LCMS (M+1)=408.6.

Synthesis of Intermediate 12-i

Boc-4-amino-D-phenylalanine methyl ester (11-iii, 929 mg, 3.16 mmol, 1.0eq) was dissolved in DCE (16 mL, 0.2 M) and treated with valeraldehyde(336 μL, 3.16 mmol, 1.0 eq), NaBH(OAc)₃ (1003 mg, 4.73 mmol, 1.5 eq) andAcOH (180 μL, 2.15 mmol, 1.0 eq). The reaction was stirred at roomtemperature for 18 h, after which it was quenched by the addition ofsaturated aqueous NaHCO₃ followed by 1 h of stirring. The layers wereseparated and the aqueous phase was washed with DCM (2×10 mL). Theorganic layers were combined, dried over Na₂SO₄, filtered andconcentrated. The residue was purified by flash chromatography(EtOAc/hexanes) to afford intermediate 12-i (738 mg, 2.02 mmol, 64%) asa pale yellow solid. ¹H NMR (400 MHz, d₄-MeOH) δ=6.94 (d, J=8.4 Hz, 2H),6.58 (d, J=8.5 Hz, 2H), 4.31-4.23 (m, 1H), 3.67 (s, 3H), 3.04 (t, J=7.2Hz, 2H), 2.93 (dd, J=13.9, 5.8 Hz, 1H), 2.78 (dd, J=13.9, 8.4 Hz, 1H),1.66-1.52 (m, 2H), 1.42-1.34 (m, 4H), 1.39 (s, 9H), 0.93 (t, J=7.0 Hz,3H).

Synthesis of Intermediate 14-i

Boc-4-amino-D-phenylalanine methyl ester (11-iii, 1.00 g, 3.39 mmol, 1.0eq) was dissolved in DCM (20 mL) and treated with pyridine (0.30 mL,3.73 mmol, 1.1 eq) and phenylsulfonyl chloride (0.43 mL, 3.39 mmol, 1.0eq). The reaction was stirred at room temperature for 24 h, after whichis was quenched by the addition of saturated aqueous NH₄Cl. The layerswere separated and the organic layer was washed with saturated aqueousNaHCO₃ and brine, dried over Na₂SO₄, filtered and concentrated. Theresidue was purified by flash chromatography (EtOAc/hexanes) to affordintermediate 14-i (1.39 g, 3.20 mmol, 94%) as a yellow oil. ¹H NMR (400MHz, d₄-MeOH) δ=7.74 (d, J=7.5 Hz, 2H), 7.57 (t, J=7.5 Hz, 1H), 7.48 (t,J=7.5 Hz, 2H), 7.08 (d, J=8.4 Hz, 2H), 7.02 (d, J=8.4 Hz, 2H), 4.29 (dd,J=8.7, 5.4 Hz, 1H), 3.65 (s, 3H), 3.02 (dd, J=8.7, 5.4 Hz, 1H), 2.83(dd, J=13.8, 5.4 Hz, 1H), 1.39 (s, 9H).

Synthesis of Intermediate 15-i

Boc-4-amino-D-phenylalanine methyl ester (11-iii, 1.00 g, 3.39 mmol, 1.0eq) was dissolved in THE (20 mL) and treated with PhNCO (0.37 mL, 3.39mmol, 1.0 eq). The reaction was heated to reflux for 4 h after which itwas cooled. The mixture was concentrated to give a yellow solid. Thissolid was triturated with Et₂O. The solid was isolated by suctionfiltration yielding intermediate 15-i (1.20 g, 2.90 mmol, 87%) as awhite solid. ¹H NMR (400 MHz, d₄-MeOH) δ=7.43 (d, J=8.1 Hz, 2H), 7.38(d, J=8.1 Hz, 2H), 7.30 (t, J=8.3 Hz, 2H), 7.16 (d, J=8.3 Hz, 2H), 7.03(t, J=8.3 Hz, 1H), 4.35 (dd, J=8.7, 5.6 Hz, 1H), 3.72 (s, 3H), 3.08 (dd,J=13.8, 5.6 Hz, 1H), 2.90 (dd, J=13.8, 8.8 Hz, 1H), 1.42 (s, 9H).

Synthesis of Intermediate 38-i

Boc-4-amino-D-phenylalanine methyl ester (11-iii, 1.00 g, 3.39 mmol, 1.0eq) was dissolved in THE (20 mL) and treated with 4-Methoxyphenylisocyanate (0.44 mL, 3.39 mmol, 1.0 eq). The reaction was heated toreflux for 16 h after which it was cooled. The mixture was concentratedto give a yellow solid. This solid was triturated with Et₂O. The solidwas isolated by suction filtration yielding intermediate BD-00481-161(1.23 g, 2.77 mmol, 83%) as a white powder. ¹H NMR (400 MHz, d₄-MeOH)δ=7.36 (d, J=8.2 Hz, 2H), 7.32 (d, J=9.0 Hz, 2H), 7.15 (d, J=8.2 Hz,2H), 6.89 (d, J=9.0 Hz, 2H), 4.34 (dd, J=8.8, 5.6 Hz, 1H), 3.79 (s, 3H),3.71 (s, 3H), 3.07 (dd, J=13.8, 5.6 Hz, 1H), 2.88 (dd, J=13.8, 8.9 Hz,1H), 1.42 (s, 9H).

Synthesis of Intermediate 27-i

Boc-4-amino-D-phenylalanine methyl ester (11-iii, 1.00 g, 3.39 mmol, 1.0eq) was dissolved in DCM (20 mL) and treated with triethylamine (TEA,0.71 ml, 5.1 mmol, 1.5 eq). The mixture was cooled to 0° C. and thebenzoyl chloride was added (0.40 mL, 3.39 mmol, 1.0 eq). The mixture wasstirred at 0° C. for 15 minutes, and allowed to warm up to roomtemperature. The reaction was stirred at the same temperature for 3hours, after which it was quenched by the addition of saturated aqueousNH₄Cl. The layers were separated and the organic layer was washed withsaturated aqueous NaHCO₃, deionized water and brine, dried over Na₂SO₄,filtered and concentrated. This solid was triturated with Et₂O. Thesolid was isolated by suction filtration yielding intermediate 27-i(0.64 g, 1.62 mmol, 47%) as a white powder. ¹H NMR (400 MHz, d₆-DMSO)δ=10.21 (s, 1H), 7.95 (d, J=7.1 Hz, 2H), 7.69 (d, J=8.2 Hz, 2H), 7.60(t, J=7.2 Hz, 1H), 7.54 (m, 2H), 7.30 (d, J=8.0 Hz, 1H), 7.21 (d, J=8.2Hz, 2H), 4.16 (m, 1H) 3.63 (s, 3H), 2.97 (dd, J=13.6, 5.3 Hz, 1H), 2.84(m, 1H), 1.35 (s, 9H).

General Method Q: Conversion of Boc-D-Phenylalanine Methyl EsterIntermediates to Fmoc-D-Phenylalanine Intermediates

The substituted Boc-D-phenylalanine methyl ester intermediate a-i (1.0eq) was dissolved in MeOH (0.1 M) and treated with NaOH (2.0 M in H₂O,2.0 eq). The reaction was stirred at room temperature for 18 h afterwhich the solvents were evaporated. The solid residue was taken up intowater and the pH was adjusted with 1 M HCl until a precipitate formed.The precipitate was isolated by suction filtration to afford asubstituted Boc-D-phenylalanine intermediate a-ii as a solid that wasused without further purification.

The substituted Boc-D-phenylalanine a-ii (1.0 eq) was dissolved inDCM/TFA (1:1, 0.1 M) and stirred at room temperature. After 2 hours, thesolvents were evaporated to give a crude substituted D-phenylalanineintermediate a-iii. This residue was dissolved in acetone/H₂O (1:1, 0.1M). The mixture was treated with NaHCO₃ (2.0 eq) and FmocOSu (1.1 eq),and it was stirred at room temperature for 24 hours. The solvents wereremoved by evaporation and the residue was dissolved in EtOAc/H₂O. Thelayers were separated and the aqueous layer was washed with EtOAc (×2).The resulting organic layers were discarded. The aqueous layer wasacidified to pH 3 and it was extracted with EtOAc (×3). The remainingorganic layers were combined, dried over Na₂SO₄, filtered andconcentrated. The product was purified by preparative HPLC, affording asubstituted Fmoc-D-phenylalanine a-iv as a solid.

Fmoc-4-((2-morpholinoethyl)amino)-D-phenylalanine (11-v)

Intermediate 11-v was prepared from intermediate 11-iv using GeneralMethod Q to provide a beige solid in 58% yield. ¹H NMR (400 MHz,d₆-DMSO) δ=7.90 (d, J=7.5 Hz, 2H), 7.67 (t, J=8.4 Hz, 2H), 7.42 (m, 2H),7.32 (m, 2H), 7.02 (d, J=8.1 Hz, 2H), 6.53 (m, 2H), 4.24-4.04 (m, 4H),3.68 (br s, 4H), 3.25-2.55 (br m, 10H).

Fmoc-4-(n-pentylamino)-D-phenylalanine (12-ii)

Fmoc-4-(pentylamino)-D-phenylalanine (12-ii) was prepared fromintermediate 12-i using General Method Q to provide a white solid in 25%yield. ¹H NMR (400 MHz, d₄-MeOH) δ=7.78 (d, J=7.6 Hz, 2H), 7.60 (d,J=7.4 Hz, 2H), 7.40-7.35 (m, 2H), 7.34-7.24 (m, 2H), 7.02 (d, J=8.4 Hz,2H), 6.57 (d, J=8.5 Hz, 2H), 4.38-4.29 (m, 2H), 4.18-4.10 (m, 2H), 3.09(dd, J=13.9, 4.7 Hz, 1H), 2.97 (t, J=7.3 Hz, 2H), 2.81 (dd, J=13.9, 9.3Hz, 1H), 1.61-1.49 (m, 2H), 1.38-1.28 (m, 4H), 0.90 (t, J=7.0 Hz, 3H).

Fmoc-4-(phenylsulfonamido)-D-phenylalanine (14-ii)

Intermediate 14-ii was prepared from intermediate 14-i using GeneralMethod Q to provide a white solid in 23% yield. ¹H NMR (400 MHz,d₆-DMSO) δ=10.21 (br s, 1H), 7.89 (d, J=7.6 Hz, 2H), 7.72 (d, J=7.2 Hz,2H), 7.67-7.37 (m, 9H), 7.11 (d, J=8.3 Hz, 2H), 6.99 (d, J=8.2 Hz, 2H),4.24-4.01 (m, 4H), 2.96 (dd, J=13.9, 4.4 Hz, 1H), 2.76 (dd, J=13.8, 4.4Hz, 1H).

Fmoc-4-(3-phenylureido)-D-phenylalanine (15-ii)

Intermediate 15-ii was prepared from intermediate 15-i using GeneralMethod Q to provide a white solid in 58% yield. ¹H NMR (400 MHz,d₆-DMSO) δ=8.65 (s, 1H), 8.61 (s, 1H), 7.89 (d, J=7.5 Hz, 2H), 7.74-7.62(m, 3H), 7.49-7.24 (m, 9H, ArH), 7.18 (d, J=8.2 Hz, 2H), 6.97 (t, J=7.4Hz, 1H), 4.25-4.10 (m, 4H), 3.03 (dd, J=13.9, 4.5 Hz, 1H), 2.82 (dd,J=13.8, 10.4 Hz, 1H).

Fmoc-4-(3-(4-methoxyphenyl)ureido)-D-phenylalanine (38-ii)

Intermediate 38-ii was prepared from intermediate 38-i using GeneralMethod Q to provide a white solid in 54% yield. ¹H NMR (400 MHz,d₆-DMSO) δ=8.53 (s, 1H), 8.46 (s, 1H), 7.89 (d, J=7.6 Hz, 2H), 7.74 (d,J=8.4 Hz, 1H), 7.66 (t, J=8.5 Hz, 2H), 7.47-7.27 (m, 8H), 7.17 (d, J=8.1Hz, 2H), 6.87 (d, J=8.7 Hz, 2H), 4.20 (m, 4H), 3.72 (s, 3H), 3.02 (dd,J=13.7, 4.3 Hz, 1H), 2.80 (m, 1H).

Fmoc-4-(benzamidophenyl)-D-phenylalanine (27-ii)

Intermediate 27-ii was prepared from intermediate 27-i using GeneralMethod Q to provide a beige powder in 43% yield. ¹H NMR (400 MHz,d₆-DMSO) δ=12.76 (s, 1H), 10.21 (s, 1H), 7.94 (d, J=7.0 Hz, 2H), 7.89(d, J=7.6 Hz, 2H), 7.77-7.51 (m, 8H), 7.41 (q, J=7.0 Hz, 2H), 7.33 (m,2H), 7.26 (d, J=8.2 Hz, 2H), 4.28-4.10 (m, 4H), 3.07 (dd, J=13.9, 4.4Hz, 1H), 2.91-2.82 (m, 1H).

Fmoc-O-(2-morpholinoethyl)-D-tyrosine (13-ii)

Boc-D-tyrosine methyl ester (1.00 g, 3.39 mmol) was dissolved in DMF (35mL, 0.1 M) and treated with K₂CO₃ (2.34 g, 17.0 mmol, 5.0 eq) and themixture was stirred for 15 min at room temperature.4-(2-bromoethyl)morpholine hydrobromide (1.39 g, 5.08 mmol, 1.5 eq) wasadded and the mixture was stirred at room temperature for 48 h. Solidswere removed by filtration. The filtrate was diluted with water (500 mL)and it was extracted with EtOAc (3×). The organic layers were washedwith combined, washed with brine, dried over Na₂SO₄, filtered andconcentrated to afford intermediate 13-i as an orange oil (1.30 g, 3.18mmol, 94%) which was used in the next step without further purification.

Intermediate 13-i was converted to Fmoc-O-(2-morpholinoethyl)-D-tyrosine(13-ii) using General Procedure I to provide a white solid in 37% yield.¹H NMR (400 MHz, d₆-DMSO) δ=7.89 (d, J=7.5 Hz, 2H), 7.71 (d, J=8.5 Hz,1H), 7.65 (t, J=6.7 Hz, 2H), 7.42 (td, J=7.5, 2.8 Hz, 2H), 7.31 (m, 2H),7.20 (d, J=8.3 Hz, 2H), 6.86 (d, J=8.3 Hz, 2H), 4.17 (m, 6H), 3.63 (brs, 4H), 3.02 (dd, J=13.9, 4.4 Hz, 1H), 2.97-2.55 (br m, 7H).

Synthesis of Boc-Cpa-D-Dap(Fmoc)-OH (60-i)

To a cold (0° C.) stirring solution of Boc-Cpa-OH (1.0 g, 3.39 mmol) ini-PrOH (15 mL) was added HOSu (0.62 g, 5.42 mmol). After stirring for 10min, DIC (0.68 mL, 4.39 mmol) was added and continued stirring cold.Within 10 min, a white suspension resulted and stirred cold for anadditional 1.5 h. The reaction mixture was filtered, rinsed with i-PrOHand dried in vacuo to afford the desired activated acid Boc-Cpa-OSu as awhite solid (1.0 g, 2.52 mmol) in 77% yield. It was used in the nextstep without further purification. Mass calculated for(C₁₈H₂₁ClN₂O₆+H)+397.1, found 397.3.

To a cold (0° C.) stirring suspension of Boc-D-(Fmoc)Dap-OH (1.2 g, 2.72mmol) in DCM (22 mL) was added TFA (22 mL, 286 mmol). The resultingyellow solution was stirred cold for 5 min then at ambient temperaturefor an additional 30 min. The reaction solution was concentrated invacuo, successively co-evaporated with DCM (2×), PhMe (1×) and DCM (1×).The resulting pale orange solid residue was suspended in a 1:1 (v/v)mixture of DCM/DMF (26 mL) and then successively treated with DIPEA(1.85 mL, 10.6 mmol) and Boc-Cpa-OSu (1.0 g, 2.52 mmol). The pale yellowmilky mixture was stirred at ambient temperature for 16 h. The resultingpale yellow solution was concentrated in vacuo, diluted with EtOAc andthen successively washed with H₂O (2×60 mL), 0.5M HCl (1×20 mL) andbrine (2×30 mL). The organic layer was dried (MgSO₄), filtered,concentrated in vacuo and purified by column chromatography (eluted with5% MeOH/DCM) to afford the desired dipeptide Boc-Cpa-D-Dap(Fmoc)-OH asan off-white solid in 61% yield. Mass calculated for (C₃₂H₃₄ClN₃O₇+H)⁺608.2, found 608.4.

TABLE 1 Intermediate Linear Peptides Prepared Using Example 1Intermediate Peptide Intermediate Linear Peptide Sequence 1-iH-Cpa-D-Cys-Tyr-D-Cit-Lys-Thr-Cys-D-Tyr-NH₂ 2-iH-Cpa-D-Cys-Tyr-D-HoCit-Lys-Thr-Cys-D-Tyr-NH₂ 3-iH-Cpa-D-Cys-Tyr-D-Lys(N^(ε)-nicotinoyl)-Lys-Thr-Cys-D-Tyr-NH₂ 4-iH-Cpa-D-Cys-Tyr-D-Phe(4-carbamoyl)-Lys-Thr-Cys-D-Tyr-NH₂ 5-iH-Cpa-D-Cys-Tyr-D-Phe(4-aminomethyl)-Lys-Thr-Cys-D-Tyr-NH₂ 6-iH-Cpa-D-Cys-Tyr-D-Phe(4-acetamidomethyl)-Lys-Thr-Cys-D-Tyr-NH₂ 7-iH-Cpa-D-Cys-Tyr-D-Phe(4-ureidomethyl)-Lys-Thr-Cys-D-Tyr-NH₂ 8-iH-Cpa-D-Cys-Tyr-D-Aph(Gly)-Lys-Thr-Cys-D-Tyr-NH₂ 9-iH-Cpa-D-Cys-Tyr-D-Aph(Gly-Ac)-Lys-Thr-Cys-D-Tyr-NH₂ 10-iH-Cpa-D-Cys-Tyr-D-Aph(Pro)-Lys-Thr-Cys-D-Tyr-NH₂ 11-viH-Cpa-D-Cys-Tyr-D-Aph(2-(4-morpholinyl)ethyl)-Lys-Thr-Cys-D-Tyr-NH₂12-vi H-Cpa-D-Cys-Tyr-D-Phe(4-n-pentylamino)-Lys-Thr-Cys-D-Tyr-NH₂13-iiiH-Cpa-D-Cys-Tyr-D-Tyr(2-(4-morpholinyl)ethyl)-Lys-Thr-Cys-D-Tyr-NH₂14-vi H-Cpa-D-Cys-Tyr-D-Aph(benzenesulfonyl)-Lys-Thr-Cys-D-Tyr-NH₂ 15-viH-Cpa-D-Cys-Tyr-D-Phe(4-phenylureido)-Lys-Thr-Cys-D-Tyr-NH₂ 16-iH-Cpa-D-Cys-Tyr-D-Aph(Ser)-Lys-Thr-Cys-D-Tyr-NH₂ 17-iH-Cpa-D-Cys-Tyr-D-Aph(Lys)-Lys-Thr-Cys-D-Tyr-NH₂ 18-iH-Cpa-D-Cys-Tyr-D-Aph(Asp)-Lys-Thr-Cys-D-Tyr-NH₂ 19-iH-Cpa-D-Cys-Tyr-D-Aph(Asn)-Lys-Thr-Cys-D-Tyr-NH₂ 20-iH-Cpa-D-Cys-Tyr-D-Aph(Glu)-Lys-Thr-Cys-D-Tyr-NH₂ 21-iH-Cpa-D-Cys-Tyr-D-Aph(Gln)-Lys-Thr-Cys-D-Tyr-NH₂ 22-iH-Cpa-D-Cys-Tyr-D-Aph(Cit)-Lys-Thr-Cys-D-Tyr-NH₂ 23-iH-Cpa-D-Cys-Tyr-D-Aph(Val)-Lys-Thr-Cys-D-Tyr-NH₂ 24-iH-Cpa-D-Cys-Tyr-D-Phe(4-carbamoyl)-Lys-(N^(ε)-Me)-Thr-Cys-D-Tyr-NH₂

TABLE 2 Resin-Bound Intermediate Linear Peptides Prepared Using Example2 Intermediate Peptide Resin-Bound Intermediate Linear Peptide Sequence25-iFmoc-Cpa-D-Cys(Trt)-Tyr(tBu)-D-Phe(4-phenylureido)-Lys(N^(ε)-Boc-N^(ε)-Me)-Thr(tBu)-Cys(Trt)-D-Tyr(t-Bu)-NH-MBHA resin 26-iFmoc-Cpa-D-Cys(Trt)-Tyr(tBu)-D-Phe(4-carbamoyl)-Lys(N^(ε)-Ac)-Thr(tBu)-Cys(Trt)-D-Tyr(t-Bu)-NH-MBHA resin 27-iiiFmoc-Cpa-D-Cys(Trt)-Tyr(tBu)-D-Phe(4-benzamidophenyl)-Lys(Boc)-Thr(tBu)-Cys(Trt)-D-Tyr(t-Bu)-NH-MBHA resin 28-iFmoc-Cpa-D-Cys(Trt)-Tyr(tBu)-D-Phe(4-(4-methoxyphenyl)ureido)-Lys(Boc)-Thr(tBu)-Cys(Trt)-D-Tyr(t-Bu)-NH-MBHA resin 29-iFmoc-Cpa-D-Cys(Trt)-Tyr(tBu)-D-Phe(4-carbamoyl)-Arg(Pbf)-Thr(tBu)-Cys(Trt)-D-Tyr(t-Bu)-NH-MBHA resin 30-iFmoc-Cpa-D-Cys(Trt)-Tyr(tBu)-D-Lys(N^(ε)-nicotinoyl)-Lys(N^(ε)-Boc-N^(ε)-Me)-Thr(tBu)-Cys(Trt)-D-Tyr(t-Bu)-NH-MBHA resin 31-iFmoc-Cpa-D-Cys(Trt)-Tyr(tBu)-D-Cit-Lys(N^(ε)-Boc-N^(ε)-Me)-Thr(tBu)-Cys(Trt)-D-Tyr(t-Bu)-NH-MBHA resin 32-iFmoc-Cpa-D-Cys(Trt)-Tyr(tBu)-D-Phe(4-carbamoyl)-Lys(N^(ε)-diMe)-Thr(tBu)-Cys(Trt)-D-Tyr(t-Bu)-NH-MBHA resin 33-iBoc-Cpa-D-Cys(Trt)-Tyr(tBu)-D-Phe(4-carbamoyl)-Lys(Boc)-Val-Cys(Trt)-D-Tyr(t-Bu)-NH-MBHA resin 34-iBoc-Cpa-D-Cys(Trt)-Tyr(tBu)-D-Phe(4-carbamoyl)-Lys(Boc)-Tle-Cys(Trt)-D-Tyr(t-Bu)-NH-MBHA resin 35-iBoc-Cpa-D-Cys(Trt)-Phe-D-Phe(4-carbamoyl)-Lys(Boc)-Thr(tBu)-Cys(Trt)-D-Tyr(t-Bu)-NH-MBHA resin 36-iBoc-Cpa-D-Cys(Trt)-Cpa-D-Phe(4-carbamoyl)-Lys(Boc)-Thr(tBu)-Cys(Trt)-D-Tyr(t-Bu)-NH-MBHA resin 37-iBoc-Cpa-D-Cys(Trt)-Tyr(tBu)-D-Phe(4-carbamoyl)-Lys(Boc)-Ser(tBu)-Cys(Trt)-D-Tyr(t-Bu)-NH-MBHA resin 38-iiiBoc-Cpa-D-Cys(Trt)-Tyr(Me)-D-Phe(4-carbamoyl)-Lys(Boc)-Thr(tBu)-Cys(Trt)-D-Tyr(t-Bu)-NH-MBHA resin 39-iBoc-Cpa-Cys(Trt)-Tyr(tBu)-D-Phe(4-carbamoyl)-Lys(Boc)-Thr(tBu)-Cys(Trt)-D-Tyr(t-Bu)-NH-MBHA resin 40-iBoc-Cpa-D-Cys(Trt)-Tyr(tBu)-D-Phe(4-carbamoyl)-Lys(Boc)-Thr(tBu)-Cys(Trt)-D-Phe-NH-MBHA resin 41-iBoc-Cpa-D-Cys(Trt)-Phe-D-Phe(4-carbamoyl)-Lys(Boc)-Thr(tBu)-Cys(Trt)-D-Phe-NH-MBHA resin 42-iBoc-Cpa-D-Cys(Trt)-Tyr(tBu)-D-Phe(4-carbamoyl)-Lys(Boc)-Thr(tBu)-Cys(Trt)-D-Cpa-NH-MBHA resin 43-iBoc-Cpa-D-Cys(Trt)-Cpa-D-Phe(4-carbamoyl)-Lys(Boc)-Thr(tBu)-Cys(Trt)-D-Cpa-NH-MBHA resin 44-iBoc-Cpa-D-Cys(Trt)-Tyr(tBu)-D-Phe(4-carbamoyl)-Lys(Boc)-Thr(tBu)-Cys(Trt)-D-Tyr(Me)-NH-MBHA resin 45-iBoc-Cpa-D-Cys(Trt)-Tyr(Me)-D-Phe(4-carbamoyl)-Lys(Boc)-Thr(tBu)-Cys(Trt)-D-Tyr(Me)-NH-MBHA resin 46-iBoc-Cpa-D-Cys(Trt)-Try(tBu)-D-Phe(4-carbamoyl)-Lys(N^(ε)-Boc-N^(ε)-Me)-Thr(tBu)-Cys(Trt)-D-Cpa-NH-MBHA resin 47-iBoc-Cpa-D-Cys(Trt)-Cpa-D-Phe(4-carbamoyl)-Lys(N^(ε)-Boc-N^(ε)-Me)-Thr(tBu)-Cys(Trt)-D-Cpa-NH-MBHA resin 48-iBoc-Cpa-D-Cys(Trt)-Cpa-D-Phe(4-carbamoyl)-Lys(N^(ε)-Boc-N^(ε)-Me)-Thr(tBu)-Cys(Trt)-D-Tyr(tBu)-NH-MBHA resin 49-i Boc-

-Ala-Cpa-D-Cys(Trt)-Tyr(t-Bu)-D-Phe(4-carbamoyl)-Lys(N^(ε)-Boc-N^(ε)-Me)-Thr(t-Bu)-Cys(Trt)-D-Tyr(t-Bu)-NH-MBHA resin 50-iPh(CO)NHCH₂(CO)-Cpa-D-Cys(Trt)-Tyr(t-Bu)-D-Phe(4-carbamoyl)-Lys(N^(ε)-Boc-N^(ε)-Me)-Thr(t-Bu)-Cys(Trt)-D-Tyr(t-Bu)-NH-MBHA resin 51-iPhSO₂CH₂(CO)-Cpa-D-Cys(Trt)-Tyr(t-Bu)-D-Phe(4-carbamoyl)-Lys(N^(ε)-Boc-N^(ε)-Me)-Thr(t-Bu)-Cys(Trt)-D-Tyr(t-Bu)-NH-MBHA resin 52-it-BuCH₂(CO)-Cpa-D-Cys(Trt)-Tyr(t-Bu)-D-Phe(4-carbamoyl)-Lys(N^(ε)-Boc-N^(ε)-Me)-Thr(t-Bu)-Cys(Trt)-D-Tyr(t-Bu)-NH-MBHA resin 53-i2-Pyridyl(CO)-Cpa-D-Cys(Trt)-Tyr(t-Bu)-D-Phe(4-carbamoyl)-Lys(N^(ε)-Boc-N^(ε)-Me)-Thr(t-Bu)-Cys(Trt)-D-Tyr(t-Bu)-NH-MBHA resin 54-iH₂N(CO)(CH₂)₂(CO)-Cpa-D-Cys(Trt)-Tyr(t-Bu)-D-Phe(4-carbamoyl)-Lys(N^(ε)-Boc-N^(ε)-Me)-Thr(t-Bu)-Cys(Trt)-D-Tyr(t-Bu)-NH-MBHA resin 55-iAc-Gly-Cpa-D-Cys(Trt)-Tyr(t-Bu)-D-Phe(4-carbamoyl)-Lys(N^(ε)-Boc-N^(ε)-Me)-Thr(t-Bu)-Cys(Trt)-D-Tyr(t-Bu)-NH-MBHA resin 56-iCH₃(CH₂)₄(CO)-Cpa-D-Cys(Trt)-Tyr(t-Bu)-D-Phe(4-carbamoyl)-Lys(N^(ε)-Boc-N^(ε)-Me)-Thr(t-Bu)-Cys(Trt)-D-Tyr(t-Bu)-NH-MBHA resin 57-i(Furan-2-carboxy)-Cpa-D-Cys(Trt)-Tyr(t-Bu)-D-Phe(4-carbamoyl)-Lys(N^(ε)-Boc-N^(ε)-Me)-Thr(t-Bu)-Cys(Trt)-D-Tyr(t-Bu)-NH-MBHA resin 58-iCH₃O₂C(CH₂)₂(CO)-Cpa-D-Cys(Trt)-Tyr(t-Bu)-D-Phe(4-carbamoyl)-Lys(N^(ε)-Boc-N^(ε)-Me)-Thr(t-Bu)-Cys(trt)-D-Tyr(t-Bu)-NH-MBHA resin 59-iBoc-Cpa-D-Cys(Trt)-Tyr(tBu)-D-Phe(4-CN)-Lys(Boc)-Thr(tBu)-Cys(Trt)-D-Tyr(tBu)-NH-MBHA resin 81-iCH₃SO₂-Cpa-D-Cys(Trt)-Tyr(t-Bu)-D-Phe(4-carbamoyl)-Lys(N^(ε)-Boc-N^(ε)-Me)-Thr(t-Bu)-Cys(Trt)-D-Tyr(t-Bu)-NH-MBHA resin 82-iPhSO₂-Cpa-D-Cys(Trt)-Tyr(t-Bu)-D-Phe(4-carbamoyl)-Lys(N^(ε)-Boc-N^(ε)-Me)-Thr(t-Bu)-Cys(Trt)-D-Tyr(t-Bu)-NH-MBHA resin

TABLE 3 Resin-Bound Intermediate Linear Peptides with a DisulfideIsostere Prepared Using Example 2 Intermediate Peptide Resin-BoundIntermediate Linear Peptide Sequence 60-iiBoc-Cpa-D-Dap(Fmoc)-Tyr(t-Bu)-D-Phe(4-carbamoyl)-Lys(Boc)-Thr(t-Bu)-Cys(t-Bu)-D-Tyr(t-Bu)-NH-MBHA resin 61-iBoc-Cpa-Dap(Mtt)-Tyr(t-Bu)-D-Phe(4-carbamoyl)-Lys(Boc)-Thr(t-Bu)-Cys(t-Bu)-D-Tyr(t-Bu)-NH-MBHA resin 62-iBoc-Cpa-D-Cys(t-Bu)-Tyr(t-Bu)-D-Phe(4-carbamoyl)-Lys(Boc)-Thr(t-Bu)-Dap(Mtt)-D-Tyr(t-Bu)-NH-MBHA resin 63-iBoc-Cpa-D-Cys(t-Bu)-Tyr(t-Bu)-D-Phe(4-carbamoyl)-Lys(N^(ε)-Boc-N^(ε)-Me)-Thr(t-Bu)-Dap(Mtt)-D-Tyr(t-Bu)-NH-MBHA resin 64-iFmoc-Cpa-D-Dap(N₃)-Tyr(t-Bu)-D-Phe(4-carbamoyl)-Lys(Boc)-Thr(t-Bu)-Gly(Propargyl)-D-Tyr(t-Bu)-NH-MBHA Resin 65-iBoc-Cpa-Gly(Propargyl)-Tyr(t-Bu)-D-Phe(4-carbamoyl)-Lys(Boc)-Thr(t-Bu)-Dap(N₃)-D-Tyr(t-Bu)-NH-MBHA Resin 66-iBoc-Cpa-D-Gly(Propargyl)-Tyr(t-Bu)-D-Phe(4-carbamoyl)-Lys(Boc)-Thr(t-Bu)-Dap(N₃)-D-Tyr(t-Bu)-NH-MBHA Resin 67-iBoc-Cpa-D-Gly(Allyl)-Tyr(t-Bu)-D-Phe(4-carbamoyl)-Lys(Boc)-Thr(t-Bu)-Gly(Allyl)-D-Tyr(t-Bu)-NH-MBHA Resin 68-iBoc-Cpa-Gly(Allyl)-Tyr(t-Bu)-D-Phe(4-carbamoyl)-Lys(Boc)-Thr(t-Bu)-Gly(Allyl)-D-Tyr(t-Bu)-NH-MBHA Resin 69-iBoc-Cpa-D-Asp(OAll)-Tyr(t-Bu)-D-Phe(4-carbamoyl)-Lys(Boc)-Thr(t-Bu)-Dap(Mtt)-D-Tyr(t-Bu)-NH-MBHA Resin 70-iBoc-Cpa-D-Asp(OAll)-Tyr(t-Bu)-D-(4-phenylureido)Phe-Lys(Boc)-Thr(t-Bu)-Dap(Mtt)-D-Tyr(t-Bu)-NH-MBHA Resin 71-iBoc-Cpa-D-Asp(OAll)-Tyr(t-Bu)-D-Phe(4-carbamoyl)-Lys(N^(ε)-Boc-N^(ε)-Me)-Thr(t-Bu)-Dap(Mtt)-D-Tyr(t-Bu)-NH-MBHA Resin

TABLE 4 Resin-Bound Intermediate Linear Peptides with N-MethylatedBackbones Prepared Using Example 2 Intermediate Peptide Resin-BoundIntermediate Linear Peptide Sequence 72-iBoc-Cpa-D-Cys(Trt)-Tyr(tBu)-D-Phe(4-carbamoyl)-(N^(α)-Me)Lys(Boc)-Thr(tBu)-Cys(Trt)-D-Tyr(tBu)-NH-MBHA resin 73-iBoc-Cpa-D-Cys(Trt)-Tyr(tBu)-D-Phe(4-carbamoyl)-Lys(Boc)-(N-Me)Thr(tBu)-Cys(Trt)-D-Tyr(tBu)-NH-MBHA resin 74-iBoc-Cpa-D-Cys(Trt)-(N-Me)Tyr(tBu)-D-Phe(4-carbamoyl)-Lys(Boc)-Thr(tBu)-Cys(Trt)-D-Tyr(tBu)-NH-MBHA resin 75-iBoc-Cpa-D-Cys(Trt)-(N-Me)Tyr(tBu)-D-Phe(4-carbamoyl)-Lys(Boc)-(N-Me)Thr(tBu)-Cys(Trt)-D-Tyr(tBu)-NH-MBHA resin 76-iBoc-Cpa-D-Cys(Trt)-Tyr(tBu)-D-Phe(4-carbamoyl)-Lys(Boc)-Thr(tBu)-(N-Me)Cys(Trt)-D-Tyr(tBu)-NH-MBHA resin 77-iBoc-(N-Me)Cpa-D-Cys(Trt)-Tyr(tBu)-D-Phe(4-carbamoyl)-Lys(Boc)-Thr(tBu)-Cys(Trt)-D-Tyr(tBu)-NH-MBHA resin 78-iBoc-Cpa-D-(N-Me)Cys(Trt)-Tyr(tBu)-D-Phe(4-carbamoyl)-Lys(Boc)-Thr(tBu)-Cys(Trt)-D-Tyr(tBu)-NH-MBHA resin 79-iBoc-Cpa-D-Cys(Trt)-Tyr(tBu)-D-Phe(4-carbamoyl)-Lys(Boc)-Thr(tBu)-Cys(Trt)-D-(N-Me)Tyr(tBu)-NH-MBHA resin 80-iBoc-(N-Me)Cpa-D-Cys(Trt)-(N-Me)Tyr(tBu)-D-Phe(4-carbamoyl)-Lys(Boc)-(N-Me)Thr(tBu)-Cys(Trt)-D-(N-Me)Tyr(tBu)-NH-MBHA resin

TABLE 5 Cyclic 8-mer Compounds and Characterization Data SEQ Compound IDNo. NO. Structure Methods  1  1

Example 1 or Example 2  2  2

Example 1  3  3

Example 1  4  4

Example 1 or Example 2  5  5

Example 1  6  6

Example 1  7  7

Example 1  8  8

Example 1  9  9

Example 1 10 10

Example 1 11 11

Example 1 12 12

Example 1 13 13

Example 1 14 14

Example 1 15 15

Example 1 or Example 2 16 16

Example 1 17 17

Example 1 18 18

Example 1 19 19

Example 1 20 20

Example 1 21 21

Example 1 22 22

Example 1 23 23

Example 1 24 24

Example 1 or Example 2 25 25

Example 2 26 26

Example 2 27 27

Example 2 28 28

Example 2 29 29

Example 2 30 30

Example 2 31 31

Example 2 32 32

Example 2 33 33

Example 2 34 34

Example 2 35 35

Example 2 36 36

Example 2 37 37

Example 2 38 38

Example 2 39 39

Example 2 40 40

Example 2 41 41

Example 2 42 42

Example 2 43 43

Example 2 44 44

Example 2 45 45

Example 2 46 46

Example 2 47 47

Example 2 48 48

Example 2 49 49

Example 2 and General Method C 50 50

Example 2 and General Method C 51 51

Example 2 and General Method C 52 52

Example 2 and General Method C 53 53

Example 2 and General Method C 54 54

Example 2 and General Method C 55 55

Example 2 and General Method C 56 56

Example 2 and General Method C 57 57

Example 2 and General Method C 58 58

Example 2 and General Method C 59 59

Example 2 60 60

Example 2 and General Method D 61 61

Example 2 and General Method D 62 62

Example 2 and General Method D 63 63

Example 2 and General Method D. 64 64

Example 2 and General Method E 65 65

Example 2 and General Method E 66 66

Example 2 and General Method E 67 67

Example 2 and General Method F 68 68

Example 2 and General Method F 69 69

Example 2 and General Method G 70 70

Example 2 and General Method G 71 71

Example 2 and General Method G 72 72

Example 2 and General Method I 73 73

Example 2 and General Method I 74 74

Example 2 and General Method I 75 75

Example 2 and General Method I 76 76

Example 2 and General Method I 77 77

Example 2 and General Method I 78 78

Example 2 and General Method I 79 79

Example 2 and General Method I 80 80

Example 2 and General Method I 81 81

Example 2 and General Method J 82 82

Example 2 and General Method J

Antagonist Activity in Somatostatin Receptors (SSTRs)

The PathHunter®-Arrestin assay monitors the activation of a GPCR in ahomogenous, non-imaging assay format using a technology developed byDiscoveRx called Enzyme Fragment Complementation (EFC) withβ-galactosidase (β-Gal) as the functional reporter (Reference DiscoveRxwebsite: http://www.discoverx.com/arrestin). The enzyme is split intotwo inactive complementary portions (EA for Enzyme Acceptor and PK forProLink) expressed as fusion proteins in the cell. EA is fused toβ-Arrestin and PK is fused to the GPCR of interest. When the GPCR isactivated and β-Arrestin is recruited to the receptor, ED and EAcomplementation occurs, restoring β-Gal activity which is measured usingchemiluminescent PathHunter® Detection Reagents. For antagonistdetermination, cells were pre-incubated with the compounds followed byagonist challenge at the EC₈₀ concentration. Data was normalized to themaximal and minimal response observed in the presence of EC₈₀ ligand andvehicle. Compound activity was analyzed using CBIS data analysis suiteCheminnovation, CA). Percentage inhibition was calculated using thefollowing formula: % Inhibition=100%×(1−(mean signal of test sample−meansignal of vehicle control)/(mean signal of EC₈₀ control−mean signal ofvehicle control)). Percentage inhibition was calculated at 10concentrations in steps on a Log3 scale ranging from 1 μM down to 5e-5μM. The results were plotted for IC₅₀ calculation. IC₅₀ values forcompounds 1 to 80 are provided in Table 6. The results show thatcompounds 1-80 exhibited antagonistic activity with respect tosomatostatin type 2 (SSTR2) receptors. In addition, compoundsdemonstrated good specificity to SSTR2 versus other SSTR subtypes.

TABLE 6 IC₅₀ Data for Cyclic 8-mer Compounds IC₅₀ IC₅₀ IC₅₀ IC₅₀ IC₅₀SSTR1 SSTR2 SSTR3 SSTR4 SSTR5 Compound (uM) (uM) (uM) (uM) (uM) 1 >10.034 >1 >1 >1 2 0.181 >1 3 0.251 >1 4 >1 0.017 >1 >1 >1 5 0.213 >1 60.166 >1 7 >1 0.031 >1 >1 >1 8 0.084 >1 9 0.104 >1 10 >1 >1 11 0.243 >112 >1 0.017 >1 >1 >1 13 0.334 >1 14 >1 0.021 >1 >1 >1 15 >10.001 >1 >1 >1 16 0.234 >1 17 >1 >1 18 >1 >1 19 >1 >1 20 0.924 >121 >1 >1 22 0.417 >1 23 0.458 >1 24 >1 0.00096 >1 >1 >1 25 0.00232 26 >127 0.0347 28 0.104 29 0.398 30 0.177 31 0.0704 32 0.00246 33 0.0560 340.0434 35 0.0359 36 0.0287 37 0.0106 38 0.0244 39 >1 40 0.0162 41 0.024442 0.00984 43 0.0256 44 0.0107 45 0.0146 46 0.000398 47 0.00151 480.00131 49 0.00286 50 0.00111 51 0.00145 52 0.00173 53 0.00428 540.00233 55 0.00335 56 0.00160 57 0.00365 58 0.00236 59 0.0391 60 >161 >1 62 >1 63 >1 64 >1 65 0.688 66 >1 67 >1 68 >1 69 >1 70 >1 71 0.013372 0.00577 73 0.547 74 0.159 75 >1 76 0.400 77 0.00225 78 0.00679 790.0287 80 >1

Hypoglycemic Challenges in Streptozotocin (STZ) Diabetic RatsMethodologies

All animal experiments were approved by York University Animal CareCommittee and conducted in accordance with the Canadian Council forAnimal Care guidelines.

Male Sprague Dawley rats (initial weight 150-175 g) were purchased fromCharles River Laboratories (Montreal, QC, Canada). Rats were housed inthe York University Vivarium in a 12-hour light dark cycle. All animalswere fed a standard rodent chow diet (14% fat, 54% carbohydrates, 32%fat & 3.0 calories/g of food) and water ad libitum. After a minimum ofone week of acclimation, all animals received an intraperitonealinjection of streptozotocin (STZ) (Sigma) at a dose of 65 mg/kg bodyweight. After STZ injection, animals were provided with sugar water (5%solution) overnight. Any animals whose blood glucose was not greaterthan 10 mM within 2 days of STZ injection received a second injection.

One week after induction of diabetes, insulin treatment was initiated tomaintain blood glucose values within a reasonable glucose controlledrange in the fasted state (8-20 mM). Insulin pellets (LinChin, Toronto,ON, Canada) were implanted subcutaneously in any rat with blood glucoseover 20 mM. Briefly, animals were anesthetized via inhaled isofluraneand pellets were implanted subcutaneously within the scapular region.One week later animals underwent their first hypoglycemic challenge(Hypoglycemic Challenge #1), followed by a second hypoglycemic challenge(Hypoglycemic Challenge #2) the following week (see below). Throughoutthe study, daily animals checks were conducted to assess body weight,blood glucose as well as food/calorie consumption. A schematic of thestudy design is shown in FIG. 1.

Hypoglycemic Challenges

Animals were divided into groups and received Compound 4, or Compound 24or a corresponding dose of vehicle. Compounds were given 1 hour prior tocommencement of the hypoglycemic challenge. On the morning of thehypoglycemic challenge, food was removed from the cage and a plasmasample was collected as baseline (prior to compound/vehicleadministration), one-hour post drug/vehicle administration and at setpoints throughout the challenges. A schematic of the hypoglycemicchallenges is shown in FIGS. 2A and 2B.

For Hypoglycemic Challenge #1, hypoglycemia was induced via subcutaneousadministration of a bolus of insulin (10U Novo Rapid insulin/kg bodyweight). Blood glucose was assessed every 10 minutes via saphenous veinpuncture. Additionally, plasma was collected from the saphenous veinevery 20 minutes, until 100-minutes post insulin administration. Anadditional plasma sample was collected 4-hours post drug administration(3 hours post insulin bolus) for mass spectrometry analysis of thecompounds in plasma. If blood glucose went below 1.0 mM or animal showedsigns of distress (weakness, convolutions, seizures etc.) the challengewas stopped and the animal was provided with food or an oral gavage ofDextrose. Further details of the experimental time course for the firstchallenge are shown in FIG. 2A.

One week after the first hypoglycemia challenge, a second similarhypoglycemic challenge (Hypoglycemia Challenge #2) was conducted;however this time a higher dose of insulin was given to insure thatsevere hypoglycemia developed (20U Novo Rapid/kg body weight). Bloodglucose was monitored, every 5-10 min, via saphenous vein puncture. Whenblood glucose reached 3.5 mM, the animal was anesthetized (via inhaledisoflurane) and a saphenous vein and portal vein plasma sample werecollected. Subsequently, the animal pancreas and liver were excised andthe animal was terminated via exsanguination. Tissue was flash frozen inliquid nitrogen and maintained at −80° C. Further details of theexperimental time course for Hypoglycemia Challenge #2 are shown in FIG.2B.

Results Hypoglycemic Challenge #1

FIG. 3 shows blood glucose (BG) values measured over time in STZdiabetic Sprague Dawley rats treated at t=−60 min with either vehiclecontrol, Compound 4, or Compound 24, then treated with insulin 10 U/kgat t=0 min. The time course demonstrates that the diabetic ratsexperience a BG drop in response to insulin therapy, which can result inhypoglycemia (defined as a BG threshold of 3.9 mM or below). 2-Way ANOVAanalysis demonstrates that Compound 24 has significantly higher BGvalues in the first 40 minutes after insulin therapy, compared with theVehicle Control group, while the Compound 4 group had higher values inthe first 20 minutes. From the BG vs time curves, the extent ofhypoglycemia is represented by the area under the curve (AUC) for theblood glucose values over time. The AUC is calculated as the area belowthe 3.9 mM threshold value (inset graph). The AUC value was highest forthe vehicle control group (132 mM×min), and lowest for the group treatedwith Compound 24 (55 mM×min). The graph represents the average ±standarddeviation values of BG. Sample sizes were N=9 for Compound 4 andCompound 24 treatment groups, and N=6 for the Vehicle Control group.

Time to Onset of Hypoglycemia in Hypoglycemia Challenge #1

FIG. 4 shows the time to onset of hypoglycemia which was determined byinterpolating the data from FIG. 3 to determine the time at which eachsubject's BG first reached 3.9 mM. Rats in Vehicle Control groupexperienced onset of hypoglycemia on average 43 minutes after receivinga 10 U/kg insulin dose, whereas rats treated with Compound 24experienced a delay in hypoglycemia onset, at an average 97 minutesafter insulin administration. The results show that treatment can delaythe onset of insulin induced hypoglycemia. This graph presents theaverage ±standard deviation values of time to hypoglycemia onset. Samplesizes were N=9 for Compound 4 and Compound 24 treatment groups, and N=6for the Vehicle Control group.

Proportion of Rats in Hypoglycemia as a Function of Time

FIG. 5 shows the data from FIG. 3, presented as a survival curve,indicating the proportion of rats from each group that were inhypoglycemia (defined as the BG threshold of 3.9 mM) at any given time.The graph illustrates that rats from the Vehicle Control group were thefirst to become hypoglycemic (2 of 6 rats became hypoglycemic 20 minutesafter receiving insulin), and that 100% of the group reachedhypoglycemia by 100 minutes after receiving insulin. In contrast, forrats treated with Compound 24, 2 of 9 rats first became hypoglycemia at40 minutes. In the Compound 24 treated group, 1 rat never becamehypoglycemic. The results show that treatment can delay or reduce thefrequency of hypoglycemia.

Proportion of Rats in Severe Hypoglycemia as a Function of Time

FIG. 6 shows the data from FIG. 3, presented as a survival curve,indicating the proportion of rats from each group that were in severehypoglycemia (defined as the BG threshold of 1.9 mM) at any given time.The graph illustrates that of rats from the Vehicle Control group, 50%experienced severe hypoglycemia within 100 minutes after receivinginsulin. In contrast, for rats treated with Compound 24, the rate ofonset and incidence of severe hypoglycemia was lower (44% after 150minutes). For Compound 4, the rate was 33% after 130 minutes. Theresults show that treatment can delay or reduce the frequency of severehypoglycemia.

Glucagon Responses to Hypoglycemia in Hypoglycemia Challenge #1

FIGS. 7A and 7B show the response of glucagon to hypoglycemia inHypoglycemia Challenge #1. Glucagon values were collected in parallelwith BG sampling (BG results shown in FIG. 3 to FIG. 6). From glucagonmeasures in saphenous blood samples collected at basal condition (t=−60min), and from 0 to 100 minutes after insulin dosing, the basal and peakvalues measured over this time course is shown in FIG. 7A, with Tmaxvalues describing the average time of peak response in each group shownin FIG. 7B. Peak glucagon values were 83, 180 and 175 pg/mL in theVehicle Control, Compound 4 and Compound 24 treatment groups,respectively. The difference in peak values for treatment groupscompared to Vehicle Control was significant (Bonferroni post-hoc test,2-Way ANOVA). Average Tmax values were in the range of 15-36 minutesafter insulin dosing for all groups. The results indicate that treatmentresulted in a stronger glucagon secretory response to hypoglycemia indiabetic rats, compared to the vehicle control group. Graphs presentaverage ±standard deviation values. Sample sizes were N=9 for Compound 4and Compound 24 treatment groups, and N=6 for the Vehicle Control group.

Hypoglycemic Challenge #2 Portal Blood Glucagon Concentration atHypoglycemia During Hypoglycemia Challenge #2

FIG. 8 shows the portal glucagon concentrations at hypoglycemia duringHypoglycemia Challenge #2. One week after receiving a first insulinchallenge to induce hypoglycemia (FIGS. 3-7), rats received a 20 U/kginsulin challenge to induce hypoglycemia. Once hypoglycemia was achieved(target BG 2.5 mM), the glucagon concentration in the subjects' portalblood was determined. The average concentration in the rats treated withVehicle Control was 117 pg/mL. In contrast, the average values in thegroups treated with Compound 4 or Compound 24 were 462 and 801 pg/mL,respectively, indicating that treatment promoted glucagon secretion fromthe pancreas of diabetic rats in hypoglycemia. In the Vehicle Controlgroup, one sample was excluded from analysis due to contamination (N=5)while the treatment groups included N=9 subjects each. The Box plotshows the median, interquartile range and Whiskers indicate the minimumand maximum values for each group.

INFORMAL SEQUENCE TABLE WITH FREE TEXT SEQ ID NO: 1

H-Cpa-cyclo[DCys- Tyr-DCit-Lys-Thr- Cys]-DTyr- NH₂ SEQ ID NO: 2

H-Cpa-cyclo[DCys- Tyr-DHoCit-Lys- Thr-Cys]- DTyr-NH₂ SEQ ID NO: 3

H-Cpa-cyclo[DCys- Tyr-D-(N^(ϵ)- nicotinoyl)Lys-Lys- Thr-Cys]-DTyr-NH₂SEQ ID NO: 4

H-Cpa-cyclo[DCys- Tyr-D-(4- carbamoyl)Phe-Lys- Thr-Cys]-DTyr-NH₂ SEQ IDNO: 5

H-Cpa-cyclo[DCys- Tyr-D-(4- aminomethyl)Phe- Lys-Thr-Cys]- DTyr-NH₂ SEQID NO: 6

H-Cpa-cyclo[DCys- Tyr-D-(4- acetamido- methyl)Phe- Lys-Thr-Cys]-DTyr-NH₂ SEQ ID NO: 7

H-Cpa-cyclo[DCys- Tyr-D-(4- ureidomethyl) Phe-Lys- Thr-Cys]-DTyr-NH₂ SEQID NO: 8

H-Cpa-cyclo[DCys- Tyr-D-4-(Gly) Aph-Lys- Thr-Cys]-DTyr-NH₂ SEQ ID NO: 9

H-Cpa-cyclo[DCys- Tyr-D-4-(Gly- Ac)Aph- Lys-Thr-Cys]- DTyr-NH₂ SEQ IDNO: 10

H-Cpa-cyclo[DCys- Tyr-D-4-(Pro) Aph-Lys- Thr-Cys]- DTyr-NH₂ SEQ ID NO:11

H-Cpa-cyclo [DCys-Tyr- D-4-(2-(4- morpholinyl) ethyl)Aph- Lys-Thr-Cys]-DTyr-NH₂ SEQ ID NO: 12

H-Cpa-cyclo[DCys- Tyr-D-4-(n- pentylamino) Phe-Lys-Thr- Cys]-DTyr-NH₂SEQ ID NO: 13

H-Cpa-cyclo[DCys- Tyr-D-(2-(4- morpholinyl)ethyl) Tyr-Lys-Thr-Cys]-DTyr-NH₂ SEQ ID NO: 14

H-Cpa-cyclo[DCys- Tyr-D-4- (benzenesulfonyl) Aph-Lys-Thr- Cys]-DTyr-NH₂SEQ ID NO: 15

H-Cpa-cyclo[DCys- Tyr-D-4- (phenylureido) Phe-Lys-Thr-Cys]- DTyr-NH₂ SEQID NO: 16

H-Cpa-cyclo[DCys- Tyr-D-4-(Ser) Aph-Lys-Thr- Cys]-DTyr-NH₂ SEQ ID NO: 17

H-Cpa-cyclo[DCys- Tyr-D-4-(Lys) Aph-Lys-Thr- Cys]-DTyr-NH₂ SEQ ID NO: 18

H-Cpa-cyclo[DCys- Tyr-D-4-(Asp) Aph-Lys-Thr- Cys]-DTyr-NH₂ SEQ ID NO: 19

H-Cpa-cyclo[DCys- Tyr-D-4-(Asn) Aph-Lys-Thr- Cys]-DTyr-NH₂ SEQ ID NO: 20

H-Cpa-cyclo[DCys- Tyr-D-4-(Glu)Aph- Lys-Thr-Cys]- DTyr-NH₂ SEQ ID NO: 21

H-Cpa-cyclo[DCys- Tyr-D-4-(Gln)Aph- Lys-Thr-Cys]- DTyr-NH₂ SEQ ID NO: 22

H-Cpa-cyclo[DCys- Tyr-D-4-(Cit)Aph- Lys-Thr-Cys]- DTyr-NH₂ SEQ ID NO: 23

H-Cpa-cyclo[DCys- Tyr-D-4-(Val)Aph- Lys-Thr-Cys]- DTyr-NH₂ SEQ ID NO: 24

H-Cpa-cyclo[DCys- Tyr-D-(4- carbamoyl)Phe- (N^(ϵ)-Me)Lys-Thr- Cys]-DTyr-NH₂ SEQ ID NO: 25

H-Cpa-cyclo[DCys- Tyr-D-4- (phenylureido)Phe- (N—Me)Lys-Thr-Cys]-DTyr-NH₂ SEQ ID NO: 26

H-Cpa-cyclo[DCys- Tyr-D-(4- carbamoyl)Phe-(N- Acetyl)Lys-Thr-Cys]-DTyr-NH₂ SEQ ID NO: 27

H-Cpa-cyclo[DCys- Tyr-D-(4- Benzamidophenyl) Phe-Lys-Thr- Cys]-DTyr-NH₂SEQ ID NO: 28

H-Cpa-cyclo[DCys- Tyr-D-(4-(4- methoxyphenyl) ureido) Phe-Lys-Thr-Cys]-DTyr-NH₂ SEQ ID NO: 29

H-Cpa-cyclo[DCys- Tyr-D-(4- carbamoyl)Phe-Arg- Thr-Cys]-DTyr-NH₂ SEQ IDNO: 30

H-Cpa-cyclo[DCys- Tyr-D-(N- nicontinoyl)Lys- (N—Me)Lys-Thr-Cys]-DTyr-NH₂ SEQ ID NO: 31

H-Cpa-cyclo[DCys- Tyr-D-Cit- (N—Me)Lys-Thr- Cys]-DTyr-NH₂ SEQ ID NO: 32

H-Cpa-cyclo[DCys- Tyr-D-(4- carbamoyl)Phe (N-diMe) Lys-Thr-Cys]-DTyr-NH₂ SEQ ID NO: 33

H-Cpa-cyclo[DCys- Tyr-D-4- (carbamoyl)Phe-Lys- Val-Cys]-DTyr-NH₂ SEQ IDNO: 34

H-Cpa-cyclo[DCys- Tyr-D-4- (carbamoyl)Phe-Lys- tBu-Gly-Cys]-DTyr- NH₂SEQ ID NO: 35

H-Cpa-cyclo[DCys- Phe-D-(4- carbamoyl)Phe-Lys- Thr-Cys]-DTyr-NH₂ SEQ IDNO: 36

H-Cpa-cyclo[DCys- Cpa-D-(4- carbamoyl)Phe-Lys- Thr-Cys]-DTyr-NH₂ SEQ IDNO: 37

H-Cpa-cyclo[DCys- Tyr-D-(4- carbamoyl)Phe-Lys- Ser-Cys]-DTyr-NH₂ SEQ IDNO: 38

H-Cpa-cyclo[DCys- 4-OMe-Phe-D-(4- carbamoyl)Phe-Lys- Thr-Cys]-DTyr-NH₂SEQ ID NO: 39

H-Cpa-cyclo[Cys- Tyr-D-(4- carbamoyl)Phe- Lys-Thr-Cys]- DTyr-NH₂ SEQ IDNO: 40

H-Cpa-cyclo[DCys- Tyr-D-(4- carbamoyl)Phe-Lys- Thr-Cys]-DPhe-NH₂ SEQ IDNO: 41

H-Cpa-cyclo[DCys- Phe-D-(4- carbamoyl)Phe-Lys- Thr-Cys]-DPhe-NH₂ SEQ IDNO: 42

H-Cpa-cyclo[DCys- Tyr-D-(4- carbamoyl)Phe- Lys-Thr-Cys]- 4-Cl-D-Phe-NH₂SEQ ID NO: 43

H-Cpa-cyclo[DCys- 4-Cl-Phe-D-(4- carbamoyl)Phe-Lys- Thr-Cys]-4-Cl-D-Phe-NH₂ SEQ ID NO: 44

H-Cpa-cyclo[DCys- Tyr-D-(4- carbamoyl)Phe-Lys- Thr-Cys]-4-OMe-D- Phe-NH₂SEQ ID NO: 45

H-Cpa-cyclo[DCys- 4-OMe-Phe-D-(4- carbamoyl)Phe-Lys- Thr-Cys]-4-OMe-D-Phe-NH₂ SEQ ID NO: 72

H-Cpa-cyclo[DCys- Tyr-D-(4- carbamoyl)Phe- (N-alpha-Me)Lys- Thr-Cys]-DTyr-NH₂ SEQ ID NO: 66

H-Cpa-cyclo[DXaa2- Tyr-Xaa4-Lys-Thr- Xaa7]-DTyr-NH₂ SEQ ID NO: 65

H-Cpa-cyclo[LXaa2- Tyr-Xaa4-Lys-Thr- Xaa7]-DTyr-NH₂ SEQ ID NO: 64

H-Cpa-cyclo[DXaa2- Tyr-Xaa4-Lys-Thr- Xaa7]-DTyr-NH₂ SEQ ID NO: 67

H-Cpa-cyclo[DXaa2- Tyr-Xaa4-Lys-Thr- Xaa7]-DTyr-NH₂ SEQ ID NO: 68

H-Cpa-cyclo[Xaa2- Tyr-Xaa4-Lys- Thr-Xaa7]- DTyr-NH₂ SEQ ID NO: 69

H-Cpa-cyclo [DDap-Tyr- DPhe(4-CONH₂)- Lys-Thr-Asp]- DTyr-NH₂ SEQ ID NO:60

H-Cpa-cyclo [DDap-Tyr- DPhe(4-CONH₂)- Lys-Thr-Cys]- DTyr-NH₂ SEQ ID NO:70

H-Cpa-cyclo [DDap-Tyr- Xaa4-Lys- Thr-Asp]- DTyr-NH₂ SEQ ID NO: 71

H-Cpa-cyclo [DDap-Tyr- DPhe(4-CONH₂)- Lys(Me)-Thr- Asp]-DTyr-NH₂ SEQ IDNO: 54

Xaa0-Cpa-cyclo [Xaa2-Tyr- DPhe(4-CONH₂)- Lys(Me)-Thr- Xaa7]-DTyr-NH₂ SEQID NO: 55

Ac-Gly-Cpa-cyclo [Xaa2-Tyr-DPhe(4- CONH₂)-Lys(Me)- Thr-Xaa7]- DTyr-NH₂SEQ ID NO: 61

H-Cpa-cyclo[Dap- Tyr-DPhe (4-CONH₂)- Lys-Thr-Cys]- DTyr-NH₂ SEQ ID NO:49

H-βAla-Cpa-cyclo [DCys-Tyr-DPhe(4- CONH₂)-Lys(Me)- Thr-Cys]- DTyr-NH₂SEQ ID NO: 51

Xaa0-Cpa- cyclo[DCys- Tyr-DPhe (4-CONH₂)- Lys(Me)-Thr-Cys]- DTyr-NH₂ SEQID NO: 50

Xaa0-Cpa-cyclo [DCys-Tyr- DPhe(4-CONH₂)- Lys(Me)-Thr-Cys]- DTyr-NH₂ SEQID NO: 52

Xaa0-Cpa-cyclo [DCys-Tyr-DPhe(4- CONH₂)- Lys(Me)-Thr-Cys]- DTyr-NH₂ SEQID NO: 53

Xaa0-Cpa-cyclo [DCys-Tyr-DPhe (4-CONH₂)- Lys(Me)-Thr-Cys]- DTyr-NH₂ SEQID NO: 46

H-Cpa-cyclo[DCys- Tyr-D-(4- carbamoyl)Phe- (N—Me)Lys-Thr- Cys]-DCpa-NH₂SEQ ID NO: 47

H-Cpa-cyclo[DCys- Cpa-D-(4- carbamoyl)Phe- (N—Me)Lys-Thr- Cys]-DCpa-NH₂SEQ ID NO: 48

H-Cpa-cyclo[DCys- Cpa-D-(4- carbamoyl)Phe- (N—Me)Lys-Thr- Cys]-DTyr-NH₂SEQ ID NO: 58

Xaa0-Cpa-cyclo [DCys-Tyr-DPhe (4-CONH₂)- Lys(Me)-Thr-Cys]- DTyr-NH₂ SEQID NO: 56

Xaa0-Cpa-cyclo [DCys-Tyr-DPhe (4-CONH₂)- Lys(Me)-Thr-Cys]- DTyr-NH₂ SEQID NO: 57

Xaa0-Cpa-cyclo [DCys-Tyr-DPhe (4-CONH₂)- Lys(Me)-Thr-Cys]- DTyr-NH₂ SEQID NO: 62

H-Cpa-cyclo[DCys- Tyr-DPhe(4- CONH₂)- Lys-Thr-Dap]- DTyr-NH₂ SEQ ID NO:63

H-Cpa-cyclo [DCys-Tyr-DPhe (4-CONH₂)- Lys(Me)-Thr-Dap]- DTyr-NH₂ SEQ IDNO: 73

H-Cpa-[DCys-Tyr- DPhe(4-carbamoyl)- Lys-NMeThr- Cys]-DTyr-NH₂ SEQ ID NO:74

H-Cpa-[DCys- NMeTyr-DPhe (4-carbamoyl)- Lys-Thr-Cys]- DTyr-NH₂ SEQ IDNO: 75

H-Cpa-[DCys- NMeTyr-DPhe(4- carbamoyl)- Lys-NMeThr-Cys]- DTyr-NH₂ SEQ IDNO: 76

H-Cpa-[DCys- Tyr-DPhe (4-carbamoyl)- Lys-Thr-NMeCys]- DTyr-NH₂ SEQ IDNO: 77

H-NMeCpa- [DCys-Tyr- DPhe(4-carbamoyl)- Lys-Thr-Cys]- DTyr-NH₂ SEQ IDNO: 59

H-Cpa-[DCys- Tyr-DPhe(4-CN)- Lys-Thr-Cys]- DTyr-NH₂ SEQ ID NO: 78

H-Cpa- [NMeDCys- Tyr-DPhe (4-carbamoyl)- Lys-Thr-Cys]- DTyr-NH₂ SEQ IDNO: 79

H-Cpa-[DCys- Tyr-DPhe(4- carbamoyl)-Lys- Thr-Cys]- NMeDTyr-NH₂ SEQ IDNO: 80

H-NMeCpa-[DCys- NMeTyr-DPhe(4- carbamoyl)-Lys- NMeThr-Cys]- NMeTyr-NH₂SEQ ID NO: 81

H-N-methylsulfonyl- Cpa-DCys-Tyr- DPhe4-carbamoyl- LysMe-Thr-Cys-DTyr-NH2 SEQ ID NO: 82

H-N-phenylsulfonyl- Cpa-Dcys-Tyr- DPhe4-carbamoyl- LysMe-Thr-Cys-DTyr-NH2 SEQ ID NO: 83

*AA1*-cyclo [*AA2*-*AA3*- *AA4*-*AA5*- *AA6*-*AA7*]- *AA8*- SEQ ID NO:84

*AA9-cyclo [*AA10*- *AA11*-*AA12*- *AA13*-*AA14*- *AA15*]-*AA16*-

*AA1*

R^(N) is selected from the group consisting of: (i) H; (ii) C₁₋₆ alkyl;(iii) —C(O)R¹⁷, wherein R¹⁷ is selected from the group consisting ofC₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein theC₁₋₆alkyl is optionally substituted with one or more substituents, andwherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionallysubstituted with one or more substituents; (iv) —C(O)C₁₋₆alkylene-C(O)OR¹⁸, wherein R¹⁸ is H or C₁₋₆ alkyl optionally substitutedwith one or more substituents; (v) —C(O)C₁₋₆ alkylene-N(R²⁰)C(O)R¹⁹,wherein R¹⁹ is selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀aryl, and 5- to 10-membered heteroaryl, wherein the C₁₋₆ alkyl isoptionally substituted with one or more substituents, and wherein theC₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally substitutedwith one or more substituents, and wherein R²⁰ is H or C₁₋₆alkyl; (vi)—C(O)C₁₋₆ alkylene-NR²¹R²², wherein each of R²¹ and R²² is independentlyselected from the group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5-to 10-membered heteroaryl, wherein the C₁₋₆alkyl is optionallysubstituted with one or more substituents, and wherein the C₆₋₁₀ aryland 5- to 10-membered heteroaryl are optionally substituted with one ormore substituents; (vii) —C(O)C₁₋₆ alkylene-C(O)NR²³R²⁴, wherein each ofR²³ and R²⁴ is independently selected from the group consisting of H,C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein theC₁₋₆ alkyl is optionally substituted with one or more substituents, andwherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionallysubstituted with one or more substituents; (viii) —C(O)C₁₋₆alkylene-S(O)₂R²⁵, wherein R²⁵ is selected from the group consisting ofC₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein theC₁₋₆ alkyl is optionally substituted with one or more substituents, andwherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionallysubstituted with one or more substituents; and (ix) —S(O)₂R²⁶, whereinR²⁶ is selected from the group consisting of C₁₋₆ alkyl, C₆₋₁₀ aryl, and5- to 10-membered heteroaryl, wherein the C₁₋₆ alkyl is optionallysubstituted with one or more substituents, and wherein the C₆₋₁₀ aryland 5- to 10-membered heteroaryl are optionally substituted with one ormore substituents; R¹ is selected from the group consisting ofC₁₋₆alkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, —C₁₋₆alkylene(C₆₋₁₀aryl) and —C₁₋₆alkylene(5- to 10-membered heteroaryl), wherein theC₁₋₆alkyl, the C₆₋₁₀ aryl, the C₆₋₁₀ aryl of —C₁₋₆alkylene(C₆₋₁₀ aryl),the 5- to 10-membered heteroaryl and the 5- to 10-membered heteroaryl of—C₁₋₆alkylene(5- to 10-membered heteroaryl) are optionally substitutedwith one or more substituents, and wherein the C₁₋₆ alkylene of —C₁₋₆alkylene(C₆₋₁₀ aryl) and —C₁₋₆ alkylene(5- to 10-membered heteroaryl) isoptionally substituted with one or more substituents; chiral centre *1is in the S configuration or the R configuration;

*AA2*

R⁹ is H or C₁₋₆ alkyl; chiral centre *2 is in the S configuration or theR configuration;

*AA3*

R³ is selected from the group consisting of: (i) C₆₋₁₀ aryl which isoptionally substituted with one or more substituents; (ii) 5- to10-membered heteroaryl which is optionally substituted with one or moresubstituents; (iii) —C₁₋₆alkylene(C₆₋₁₀ aryl), wherein the C₆₋₁₀ aryl isoptionally substituted with one or more substituents, and wherein theC₁₋₆alkylene is optionally substituted with one or more substituents;(iv) —C₁₋₆ alkylene(5- to 10-membered heteroaryl), wherein the 5- to10-membered heteroaryl is optionally substituted with one or moresubstituents, and wherein the C₁₋₆alkylene is optionally substitutedwith one or more substituents; (v) —C₁₋₆ alkylene-NR²⁷C(O)R²⁸, wherein:R²⁷ is H or C₁₋₆ alkyl; R²⁸ is selected from the group consisting ofC₁₋₆alkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, and —NR²⁹R³⁰,wherein the C₁₋₆ alkyl is optionally substituted with one or moresubstituents, and wherein the C₆₋₁₀ aryl and 5- to 10-memberedheteroaryl are optionally substituted with one or more substituents; andwherein each of R²⁹ and R³⁰ is independently selected from the groupconsisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl, wherein the C₁₋₆alkyl is optionally substituted with one ormore substituents, and wherein the C₆₋₁₀ aryl and 5- to 10-memberedheteroaryl are optionally substituted with one or more substituents;(vi) —(C₆₋₁₀ arylene)-C(O)NR³¹R³² or —C₁₋₆ alkylene-(C₆₋₁₀arylene)-C(O)NR³¹R³², wherein each of R³¹ and R³² is independentlyselected from the group consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5-to 10-membered heteroaryl, wherein the C₁₋₆alkyl is optionallysubstituted with one or more substituents, and wherein the C₆₋₁₀ aryland 5- to 10-membered heteroaryl are optionally substituted with one ormore substituents; (vii) —(C₆₋₁₀ arylene)-NR³³R³⁴ or —C₁₋₆alkylene-(C₆₋₁₀ arylene)-NR³³R³⁴, wherein: each of R³³ and R³⁴ isindependently selected from the group consisting of H, C₁₋₆ alkyl, C₆₋₁₀aryl, 5- to 10-membered heteroaryl, —C(O)R³⁵, —C(O)NR³⁶R³⁷, and —SO₂R³⁸,wherein the C₁₋₆alkyl is optionally substituted with one or moresubstituents, and wherein the C₆₋₁₀ aryl and 5- to 10-memberedheteroaryl are optionally substituted with one or more substituents; R³⁵is selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, 5- to10-membered heteroaryl, and 5- to 10-membered heterocycloalkyl, whereinthe C₁₋₆alkyl is optionally substituted with one or more substituents,and wherein the C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, and 5- to10-membered heterocycloalkyl are optionally substituted with one or moresubstituents; each of R³⁶ and R³⁷ is independently selected from thegroup consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl, wherein the C₁₋₆alkyl is optionally substituted with one ormore substituents, and wherein the C₆₋₁₀ aryl and 5- to 10-memberedheteroaryl are optionally substituted with one or more substituents; andR³⁸ is selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and5- to 10-membered heteroaryl, wherein the C₁₋₆alkyl is optionallysubstituted with one or more substituents, and wherein the C₆₋₁₀ aryland 5- to 10-membered heteroaryl are optionally substituted with one ormore substituents; (viii) —(C₆₋₁₀ arylene)-SO₂NR³⁹R⁴⁰ or —C₁₋₆alkylene-(C₆₋₁₀ arylene)-SO₂NR³⁹R⁴⁰, wherein each of R³⁹ and R⁴⁰ isindependently selected from the group consisting of H, C₁₋₆alkyl, C₆₋₁₀aryl, and 5- to 10-membered heteroaryl, wherein the C₁₋₆alkyl isoptionally substituted with one or more substituents, and wherein theC₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally substitutedwith one or more substituents; (ix) —(C₆₋₁₀ arylene)-(C₁₋₆alkylene)-NR⁴¹R⁴² or —C₁₋₆ alkylene-(C₆₋₁₀ arylene)-(C₁₋₆alkylene)-NR⁴¹R⁴², wherein: each of R⁴¹ and R⁴² is independentlyselected from the group consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, 5- to10-membered heteroaryl, —C(O)R⁴³, and —C(O)NR⁴⁴R⁴⁵, wherein theC₁₋₆alkyl is optionally substituted with one or more substituents, andwherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionallysubstituted with one or more substituents; R⁴³ is selected from thegroup consisting of C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl, wherein the C₁₋₆ alkyl is optionally substituted with one ormore substituents, and wherein the C₆₋₁₀ aryl and 5- to 10-memberedheteroaryl are optionally substituted with one or more substituents; andeach of R⁴⁴ and R⁴⁵ is independently selected from the group consistingof H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, whereinthe C₁₋₆alkyl is optionally substituted with one or more substituents,and wherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl areoptionally substituted with one or more substituents; (x) —(C₆₋₁₀arylene)-OR⁴⁶ or —C₁₋₆ alkylene-(C₆₋₁₀ arylene)-OR⁴⁶, wherein R⁴⁶ isselected from the group consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and5-to 10-membered heteroaryl, wherein the C₁₋₆alkyl is optionallysubstituted with one or more substituents, and wherein the C₆₋₁₀ aryland 5- to 10-membered heteroaryl are optionally substituted with one ormore substituents; and (xi) —C₁₋₆ alkylene-(C₆₋₁₀arylene)-N(R⁴⁷)—C(O)—CHR⁴⁸—NR⁴⁹R⁵⁰, wherein R⁴⁷ is H or CH₃, R⁴⁸ is H orC₁₋₆alkyl optionally substituted with one or more substituents eachindependently selected from the group consisting of hydroxyl, —COOH,—NH₂, —C(O)NH₂, and —N(H)C(O)NH₂, and each of R⁴⁹ and R⁵⁰ isindependently H, CH₃ or acetyl; R¹⁰ is H or C₁₋₆ alkyl; chiral centre *3is in the S configuration or the R configuration;

*AA4*

R⁴ is selected from the group consisting of: (i) —C₁₋₆alkylene-N(R⁵³)C(O)NR⁵¹R⁵², wherein each of R⁵¹ and R⁵² is independentlyselected from the group consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5-to 10-membered heteroaryl, wherein the C₁₋₆ alkyl is optionallysubstituted with one or more substituents, and wherein the C₆₋₁₀ aryland 5- to 10-membered heteroaryl are optionally substituted with one ormore substituents, and wherein R⁵³ is H or C₁₋₆alkyl; (ii) —C₁₋₆alkylene-N(R⁵⁵)C(O)R⁵⁴, wherein R⁵⁴ is selected from the groupconsisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl,wherein the C₁₋₆alkyl is optionally substituted with one or moresubstituents, and wherein the C₆₋₁₀ aryl and 5- to 10-memberedheteroaryl are optionally substituted with one or more substituents, andwherein R⁵⁵ is H or C₁₋₆alkyl; (iii) —(C₆₋₁₀ arylene)-C(O)NR⁵⁶R⁵⁷ or—C₁₋₆ alkylene-(C₆₋₁₀ arylene)-C(O)NR⁵⁶R⁵⁷, wherein each of R⁵⁶ and R⁵⁷is independently selected from the group consisting of H, C₁₋₆ alkyl,C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the C₁₋₆alkyl isoptionally substituted with one or more substituents, and wherein theC₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally substitutedwith one or more substituents; (iv) —(C₆₋₁₀ arylene)-N(R⁵⁹)C(O)R⁵⁸ or—C₁₋₆ alkylene-(C₆₋₁₀ arylene)-N(R⁵⁹)C(O)R⁵⁸, wherein R⁵⁸ is selectedfrom the group consisting of C₁₋₆ alkyl, C₆₋₁₀ aryl, 5- to 10-memberedheteroaryl, and 5- to 10-membered heterocycloalkyl, wherein theC₁₋₆alkyl is optionally substituted with one or more substituents, andwherein the C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, and 5- to10-membered heterocycloalkyl are optionally substituted with one or moresubstituents, and wherein R⁵⁹ is H or C₁₋₆alkyl; (v) —(C₆₋₁₀arylene)-N(R⁶²)C(O)NR⁶⁰R⁶¹ or —C₁₋₆ alkylene-(C₆₋₁₀arylene)-N(R⁶²)C(O)NR⁶⁰R⁶¹, wherein each of R⁶⁰ and R⁶¹ is independentlyselected from the group consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5-to 10-membered heteroaryl, wherein the C₁₋₆alkyl is optionallysubstituted with one or more substituents, and wherein the C₆₋₁₀ aryland 5- to 10-membered heteroaryl are optionally substituted with one ormore substituents, and wherein R⁶² is H or C₁₋₆ alkyl; (vi) —(C₆₋₁₀arylene)-N(R⁶⁴)SO₂R⁶³ or —C₁₋₆ alkylene-(C₆₋₁₀ arylene)-N(R⁶⁴)SO₂R⁶³,wherein R⁶³ is selected from the group consisting of C₁₋₆ alkyl, C₆₋₁₀aryl, and 5- to 10-membered heteroaryl, wherein the C₁₋₆alkyl isoptionally substituted with one or more substituents, and wherein theC₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally substitutedwith one or more substituents, and wherein R⁶⁴ is H or C₁₋₆ alkyl; (vii)—(C₆₋₁₀ arylene)-SO₂NR⁶⁵R⁶⁶ or —C₁₋₆ alkylene-(C₆₋₁₀arylene)-SO₂NR⁶⁵R⁶⁶, wherein each of R⁶⁵ and R⁶⁶ is independentlyselected from the group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5-to 10-membered heteroaryl, wherein the C₁₋₆ alkyl is optionallysubstituted with one or more substituents, and wherein the C₆₋₁₀ aryland 5- to 10-membered heteroaryl are optionally substituted with one ormore substituents; (viii) —(C₆₋₁₀ arylene)-(C₁₋₆ alkylene)-NR⁶⁷R⁶⁸ or—C₁₋₆ alkylene-(C₆₋₁₀ arylene)-(C₁₋₆ alkylene)-NR⁶⁷R⁶⁸, wherein: each ofR⁶⁷ and R⁶⁸ is independently selected from the group consisting of H,C₁₋₆alkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, —C(O)R⁶⁹, and—C(O)NR⁷⁰R⁷¹, wherein the C₁₋₆ alkyl is optionally substituted with oneor more substituents, and wherein the C₆₋₁₀ aryl and 5- to 10-memberedheteroaryl are optionally substituted with one or more substituents; R⁶⁹is selected from the group consisting of C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5-to 10-membered heteroaryl, wherein the C₁₋₆alkyl is optionallysubstituted with one or more substituents, and wherein the C₆₋₁₀ aryland 5- to 10-membered heteroaryl are optionally substituted with one ormore substituents; and each of R⁷⁰ and R⁷¹ is independently selectedfrom the group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to10-membered heteroaryl, wherein the C₁₋₆ alkyl is optionally substitutedwith one or more substituents, and wherein the C₆₋₁₀ aryl and 5- to10-membered heteroaryl are optionally substituted with one or moresubstituents; (ix) —(C₆₋₁₀ arylene)-NR⁷²R⁷³ or —C₁₋₆ alkylene-(C₆₋₁₀arylene)-NR⁷²R⁷³, wherein each of R⁷² and R⁷³ is independently selectedfrom the group consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally substitutedwith one or more substituents, and wherein the C₆₋₁₀ aryl and 5- to10-membered heteroaryl are optionally substituted with one or moresubstituents; (x) —(C₆₋₁₀ arylene)-OR⁷⁴ or —C₁₋₆ alkylene-(C₆₋₁₀arylene)-OR⁷⁴, wherein R⁷⁴ is selected from the group consisting of H,C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein theC₁₋₆alkyl is optionally substituted with one or more substituents, andwherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionallysubstituted with one or more substituents; (xi) —C₁₋₆ alkylene-(C₆₋₁₀arylene)-N(R⁷⁵)—C(O)—CHR⁷⁶—NR⁷⁷R⁷⁸, wherein R⁷⁵ is H or CH₃, R⁷⁶ is H orC₁₋₆ alkyl optionally substituted with one or more substituents eachindependently selected from the group consisting of hydroxyl, —COOH,—NH₂, —C(O)NH₂, and —N(H)C(O)NH₂, and each of R⁷⁷ and R⁷⁸ isindependently H, CH₃ or acetyl; and (xii) —C₁₋₆ alkylene-(C₆₋₁₀arylene)-CN; R¹¹ is H or C₁₋₆ alkyl; chiral centre *4 is in the Sconfiguration or the R configuration;

*AA5*

R⁵ is selected from the group consisting of: (i) —NR⁷⁹R⁸⁰, wherein eachof R⁷⁹ and R⁸⁰ is independently selected from the group consisting of H,C₁₋₆ alkyl, —C(O)R⁸¹, and —C(═NR⁸²)NR⁸³R⁸⁴, or R⁷⁹ and R⁸⁰, togetherwith the N atom to which they are attached, form 5- to 10-memberedheteroaryl or 5- to 10-membered heterocycloalkyl, wherein the C₁₋₆ alkylis optionally substituted with one or more substituents, and wherein the5- to 10-membered heteroaryl and 5- to 10-membered heterocycloalkyl areoptionally substituted with one or more substituents, R⁸¹ is selectedfrom the group consisting of H, —NH₂, C₁₋₁₆ alkyl, C₁₋₆ haloalkyl, C₆₋₁₀aryl, and 5- to 10-membered heteroaryl; and each of R⁸², R⁸³, and R⁸⁴ isindependently selected from the group consisting of H, C₁₋₁₆ alkyl, C₁₋₆haloalkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl; and (ii)—N⁺R⁸⁵R⁸⁶R⁸⁷, wherein each of R⁸⁵, R⁸⁶, and R⁸⁷ is independently C₁₋₆alkyl; n¹ is 1, 2, 3, 4, 5, or 6; R¹² is H or C₁₋₆ alkyl; chiral centre*5 is in the S configuration or the R configuration;

*AA6*

R⁶ is C₁₋₆ alkyl optionally substituted with one or more substituents;R⁸ is selected from the group consisting of C₁₋₆ alkyl, C₆₋₁₀ aryl, 5-to 10-membered heteroaryl, —C₁₋₆alkylene(C₆₋₁₀ aryl) and—C₁₋₆alkylene(5- to 10-membered heteroaryl), wherein the C₁₋₆ alkyl, theC₆₋₁₀ aryl, the C₆₋₁₀ aryl of —C₁₋₆alkylene(C₆₋₁₀ aryl), the 5- to10-membered heteroaryl and the 5- to 10-membered heteroaryl of—C₁₋₆alkylene(5- to 10-membered heteroaryl) are optionally substitutedwith one or more substituents, and wherein the C₁₋₆alkylene of —C₁₋₆alkylene(C₆₋₁₀ aryl) and —C₁₋₆alkylene(5- to 10-membered heteroaryl) isoptionally substituted with one or more substituents; R¹³ is H or C₁₋₆alkyl; chiral centre *6 is in the S configuration or the Rconfiguration;

*AA7*

R¹⁴ is H or C₁₋₆ alkyl; chiral centre *7 is in the S configuration orthe R configuration;

*AA8*

R^(C) is OH or NHR¹⁶, wherein R¹⁶ is H or C₁₋₆ alkyl optionallysubstituted with one or more substituents; R¹⁵ is H or C₁₋₆ alkyl;chiral centre *8 is in the S configuration or the R configuration,

*L1*

L is selected from the group consisting of:

wherein X is S or O; and vii)

provided that:

i) when R^(C) is NH₂, R^(N) is H or —C(O)CH₂N₃, R¹ is

R³ is

R⁵ is NH₂, n¹ is 4, R⁶ is —CH(OH)(CH₃), R⁸ is

each of R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴ and R¹⁵ is H, and L is

then R⁴ is not

and ii) when R^(C) is NH₂, R^(N) is H, R¹ is

R⁵ is NH₂, n¹ is 4, R⁶ is —CH(CH₃)₂, R⁸ is —CH(OH)(CH₃), each of R⁹,R¹⁰, R¹¹, R¹², R¹³, R¹⁴ and R¹⁵ is H, and L is

then R⁴ is not

*AA9*

R^(N) is H, CH₃ or acetyl; R¹ is selected from the group consisting ofC₆₋₁₀ aryl, 5- to 10-membered heteroaryl, —C₁₋₆alkylene(C₆₋₁₀ aryl) and—C₁₋₆alkylene(5- to 10-membered heteroaryl), wherein the C₆₋₁₀ aryl andthe C₆₋₁₀ aryl of —C₁₋₆alkylene(C₆₋₁₀ aryl) and the 5- to 10-memberedheteroaryl and the 5- to 10-membered heteroaryl of —C₁₋₆ alkylene(5- to10-membered heteroaryl) are optionally substituted with one or moresubstituents, and wherein the C₁₋₆ alkylene of —C₁₋₆ alkylene(C₆₋₁₀aryl) and —C₁₋₆alkylene(5- to 10-membered heteroaryl) is optionallysubstituted with one or more substituents; chiral centre *1 is in the Sconfiguration or the R configuration;

*AA10*

Is Ala and is joined to *AA15* via *L2* wherein *L2* attaches to themethyl side chain;

*AA11*

R³ is selected from the group consisting of: (i) C₆₋₁₀ aryl which isoptionally substituted with one or more substituents; (ii) 5- to10-membered heteroaryl which is optionally substituted with one or moresubstituents; (iii) —C₁₋₆ alkylene(C₆₋₁₀ aryl), wherein the C₆₋₁₀ arylis optionally substituted with one or more substituents, and wherein theC₁₋₆alkylene is optionally substituted with one or more substituents;(iv) —C₁₋₆ alkylene(5- to 10-membered heteroaryl), wherein the 5- to10-membered heteroaryl is optionally substituted with one or moresubstituents, and wherein the C₁₋₆alkylene is optionally substitutedwith one or more substituents; (v) —NR²⁷C(O)R²⁸ or —C₁₋₆alkylene-NR²⁷C(O)R²⁸, wherein: R²⁷ is H or C₁₋₆alkyl; R²⁸ is selectedfrom the group consisting of C₁₋₆ alkyl, C₆₋₁₀ aryl, 5-to 10-memberedheteroaryl, and —NR²⁹R³⁰, wherein the C₁₋₆alkyl is optionallysubstituted with one or more substituents, and wherein the C₆₋₁₀ aryland 5- to 10-membered heteroaryl are optionally substituted with one ormore substituents; and wherein each of R²⁹ and R³⁰ is independentlyselected from the group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5-to 10-membered heteroaryl, wherein the C₁₋₆alkyl is optionallysubstituted with one or more substituents, and wherein the C₆₋₁₀ aryland 5- to 10-membered heteroaryl are optionally substituted with one ormore substituents; (vi) —(C₆₋₁₀ arylene)-C(O)NR³¹R³² or —C₁₋₆alkylene-(C₆₋₁₀ arylene)-C(O)NR³¹R³², wherein each of R³¹ and R³² isindependently selected from the group consisting of H, C₁₋₆ alkyl, C₆₋₁₀aryl, and 5- to 10-membered heteroaryl, wherein the C₁₋₆ alkyl isoptionally substituted with one or more substituents, and wherein theC₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally substitutedwith one or more substituents; (vii) —(C₆₋₁₀ arylene)-NR³³R³⁴ or —C₁₋₆alkylene-(C₆₋₁₀ arylene)-NR³³R³⁴, wherein: each of R³³ and R³⁴ isindependently selected from the group consisting of H, C₁₋₆ alkyl, C₆₋₁₀aryl, 5- to 10-membered heteroaryl, —C(O)R³⁵, —C(O)NR³⁶R³⁷, and —SO₂R³⁸,wherein the C₁₋₆alkyl is optionally substituted with one or moresubstituents, and wherein the C₆₋₁₀ aryl and 5- to 10-memberedheteroaryl are optionally substituted with one or more substituents; R³⁵is selected from the group consisting of C₁₋₆ alkyl, C₆₋₁₀ aryl, 5- to10-membered heteroaryl, and 5- to 10-membered heterocycloalkyl, whereinthe C₁₋₆alkyl is optionally substituted with one or more substituents,and wherein the C₆₋₁₀ aryl, 5-to 10-membered heteroaryl, and 5- to10-membered heterocycloalkyl are optionally substituted with one or moresubstituents; each of R³⁶ and R³⁷ is independently selected from thegroup consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl, wherein the C₁₋₆ alkyl is optionally substituted with one ormore substituents, and wherein the C₆₋₁₀ aryl and 5- to 10-memberedheteroaryl are optionally substituted with one or more substituents; andR³⁸ is selected from the group consisting of C₁₋₆ alkyl, C₆₋₁₀ aryl, and5- to 10-membered heteroaryl, wherein the C₁₋₆ alkyl is optionallysubstituted with one or more substituents, and wherein the C₆₋₁₀ aryland 5- to 10-membered heteroaryl are optionally substituted with one ormore substituents; (viii) —(C₆₋₁₀ arylene)-SO₂NR³⁹R⁴⁰ or —C₁₋₆alkylene-(C₆₋₁₀ arylene)-SO₂NR³⁹R⁴⁰, wherein each of R³⁹ and R⁴⁰ isindependently selected from the group consisting of H, C₁₋₆ alkyl, C₆₋₁₀aryl, and 5- to 10-membered heteroaryl, wherein the C₁₋₆alkyl isoptionally substituted with one or more substituents, and wherein theC₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally substitutedwith one or more substituents; (ix) —(C₆₋₁₀ arylene)-(C₁₋₆alkylene)-NR⁴¹R⁴² or —C₁₋₆ alkylene-(C₆₋₁₀ arylene)-(C₁₋₆alkylene)-NR⁴¹R⁴², wherein: each of R⁴¹ and R⁴² is independentlyselected from the group consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, 5- to10-membered heteroaryl, —C(O)R⁴³, and —C(O)NR⁴⁴R⁴⁵, wherein the C₁₋₆alkyl is optionally substituted with one or more substituents, andwherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionallysubstituted with one or more substituents; R⁴³ is selected from thegroup consisting of C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl, wherein the C₁₋₆ alkyl is optionally substituted with one ormore substituents, and wherein the C₆₋₁₀ aryl and 5- to 10-memberedheteroaryl are optionally substituted with one or more substituents; andeach of R⁴⁴ and R⁴⁵ is independently selected from the group consistingof H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, whereinthe C₁₋₆alkyl is optionally substituted with one or more substituents,and wherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl areoptionally substituted with one or more substituents; (x) —(C₆₋₁₀arylene)-OR⁴⁶ or —C₁₋₆ alkylene-(C₆₋₁₀ arylene)-OR⁴⁶, wherein R⁴⁶ isselected from the group consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5-to 10-membered heteroaryl, wherein the C₁₋₆ alkyl is optionallysubstituted with one or more substituents, and wherein the C₆₋₁₀ aryland 5- to 10-membered heteroaryl are optionally substituted with one ormore substituents; and (xi) —C₁₋₆ alkylene-(C₆₋₁₀arylene)-N(R⁴⁷)—C(O)—CHR⁴⁸—NR⁴⁹R⁵⁰, wherein R⁴⁷ is H or CH₃, R⁴⁸ is H orC₁₋₆ alkyl optionally substituted with one or more substituents eachindependently selected from the group consisting of hydroxyl, —COOH,—NH₂, —C(O)NH₂, and —N(H)C(O)NH₂, and each of R⁴⁹ and R⁵⁰ isindependently H, CH₃ or acetyl; chiral centre *3 is in the Sconfiguration or the R configuration;

*AA12*

R⁴ is selected from the group consisting of: (i) —N(R⁵³)C(O)NR⁵¹R⁵² or—C₁₋₆ alkylene-N(R⁵³)C(O)NR⁵¹R⁵², wherein each of R⁵¹ and R⁵² isindependently selected from the group consisting of H, C₁₋₆ alkyl, C₆₋₁₀aryl, and 5- to 10-membered heteroaryl, wherein the C₁₋₆alkyl isoptionally substituted with one or more substituents, and wherein theC₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally substitutedwith one or more substituents, and wherein R⁵³ is H or C₁₋₆ alkyl; (ii)—N(R⁵⁵)C(O)R⁵⁴ or —C₁₋₆ alkylene-N(R⁵⁵)C(O)R⁵⁴, wherein R⁵⁴ is selectedfrom the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to10-membered heteroaryl, wherein the C₁₋₆ alkyl is optionally substitutedwith one or more substituents, and wherein the C₆₋₁₀ aryl and 5- to10-membered heteroaryl are optionally substituted with one or moresubstituents, and wherein R⁵⁵ is H or C₁₋₆alkyl; (iii) —(C₆₋₁₀arylene)-C(O)NR⁵⁶R⁵⁷ or —C₁₋₆ alkylene-(C₆₋₁₀ arylene)-C(O)NR⁵⁶R⁵⁷,wherein each of R⁵⁶ and R⁵⁷ is independently selected from the groupconsisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl, wherein the C₁₋₆ alkyl is optionally substituted with one ormore substituents, and wherein the C₆₋₁₀ aryl and 5- to 10-memberedheteroaryl are optionally substituted with one or more substituents;(iv) —(C₆₋₁₀ arylene)-N(R⁵⁹)C(O)R⁵⁸ or —C₁₋₆ alkylene-(C₆₋₁₀arylene)-N(R⁵⁹)C(O)R⁵⁸, wherein R⁵⁸ is selected from the groupconsisting of C₁₋₆alkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, and5- to 10-membered heterocycloalkyl, wherein the C₁₋₆alkyl is optionallysubstituted with one or more substituents, and wherein the C₆₋₁₀ aryl,5- to 10-membered heteroaryl, and 5- to 10-membered heterocycloalkyl areoptionally substituted with one or more substituents, and wherein R⁵⁹ isH or C₁₋₆alkyl; (v) —(C₆₋₁₀ arylene)-N(R⁶²)C(O)NR⁶⁰R⁶¹ or —C₁₋₆alkylene-(C₆₋₁₀ arylene)-N(R⁶²)C(O)NR⁶⁰R⁶¹, wherein each of R⁶⁰ and R⁶¹is independently selected from the group consisting of H, C₁₋₆alkyl,C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the C₁₋₆alkyl isoptionally substituted with one or more substituents, and wherein theC₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally substitutedwith one or more substituents, and wherein R⁶² is H or C₁₋₆ alkyl; (vi)—(C₆₋₁₀ arylene)-N(R⁶⁴)SO₂R⁶³ or —C₁₋₆ alkylene-(C₆₋₁₀arylene)-N(R⁶⁴)SO₂R⁶³, wherein R⁶³ is selected from the group consistingof C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein theC₁₋₆alkyl is optionally substituted with one or more substituents, andwherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionallysubstituted with one or more substituents, and wherein R⁶⁴ is H or C₁₋₆alkyl; (vii) —(C₆₋₁₀ arylene)-SO₂NR⁶⁵R⁶⁶ or —C₁₋₆ alkylene-(C₆₋₁₀arylene)-SO₂NR⁶⁵R⁶⁶, wherein each of R⁶⁵ and R⁶⁶ is independentlyselected from the group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5-to 10-membered heteroaryl, wherein the C₁₋₆alkyl is optionallysubstituted with one or more substituents, and wherein the C₆₋₁₀ aryland 5- to 10-membered heteroaryl are optionally substituted with one ormore substituents; (viii) —(C₆₋₁₀ arylene)-(C₁₋₆ alkylene)-NR⁶⁷R⁶⁸ or—C₁₋₆ alkylene-(C₆₋₁₀ arylene)-(C₁₋₆ alkylene)-NR⁶⁷R⁶⁸, wherein: each ofR⁶⁷ and R⁶⁸ is independently selected from the group consisting of H,C₁₋₆alkyl, C₆₋₁₀ aryl, 5-to 10-membered heteroaryl, —C(O)R⁶⁹, and—C(O)NR⁷⁰R⁷¹, wherein the C₁₋₆alkyl is optionally substituted with oneor more substituents, and wherein the C₆₋₁₀ aryl and 5- to 10-memberedheteroaryl are optionally substituted with one or more substituents; R⁶⁹is selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and 5-to 10-membered heteroaryl, wherein the C₁₋₆alkyl is optionallysubstituted with one or more substituents, and wherein the C₆₋₁₀ aryland 5- to 10-membered heteroaryl are optionally substituted with one ormore substituents; and each of R⁷⁰ and R⁷¹ is independently selectedfrom the group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally substitutedwith one or more substituents, and wherein the C₆₋₁₀ aryl and 5- to10-membered heteroaryl are optionally substituted with one or moresubstituents; (ix) —(C₆₋₁₀ arylene)-NR⁷²R⁷³ or —C₁₋₆ alkylene-(C₆₋₁₀arylene)-NR⁷²R⁷³, wherein each of R⁷² and R⁷³ is independently selectedfrom the group consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally substitutedwith one or more substituents, and wherein the C₆₋₁₀ aryl and 5- to10-membered heteroaryl are optionally substituted with one or moresubstituents; (x) —(C₆₋₁₀ arylene)-OR⁷⁴ or —C₁₋₆ alkylene-(C₆₋₁₀arylene)-OR⁷⁴, wherein R⁷⁴ is selected from the group consisting of H,C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein theC₁₋₆ alkyl is optionally substituted with one or more substituents, andwherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionallysubstituted with one or more substituents; and (xi) —C₁₋₆alkylene-(C₆₋₁₀ arylene)-N(R⁷⁵)—C(O)—CHR⁷⁶—NR⁷⁷R⁷⁸, wherein R⁷⁵ is H orCH₃, R¹⁶ is H or C₁₋₆ alkyl optionally substituted with one or moresubstituents each independently selected from the group consisting ofhydroxyl, —COOH, —NH₂, —C(O)NH₂, and —N(H)C(O)NH₂, and each of R⁷⁷ andR⁷⁸ is independently H, CH₃ or acetyl; chiral centre *4 is in the Sconfiguration or the R configuration;

*AA13*

R⁵ is selected from the group consisting of: (i) —NR⁷⁹R⁸⁰, wherein eachof R⁷⁹ and R⁸⁰ is independently selected from the group consisting of H,C₁₋₆ alkyl, —C(O)R⁸¹, and —C(═NR⁸²)NR⁸³R⁸⁴, or R⁷⁹ and R⁸⁰, togetherwith the N atom to which they are attached, form 5- to 10-memberedheteroaryl or 5- to 10-membered heterocycloalkyl, wherein the C₁₋₆ alkylis optionally substituted with one or more substituents, and wherein the5- to 10-membered heteroaryl and 5- to 10-membered heterocycloalkyl areoptionally substituted with one or more substituents, R⁸¹ is selectedfrom the group consisting of H, —NH₂, C₁₋₁₆ alkyl, C₁₋₆ haloalkyl, C₆₋₁₀aryl, and 5- to 10-membered heteroaryl; and each of R⁸², R⁸³, and R⁸⁴ isindependently selected from the group consisting of H, C₁₋₁₆ alkyl, C₁₋₆haloalkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl; and (ii)-N+R⁸⁵R⁸⁶R⁸⁷, wherein each of R⁸⁵, R⁸⁶, and R⁸⁷ is independently C₁₋₆alkyl; n¹ is 1, 2, 3, 4, 5, or 6; R¹² is H or CH₃; chiral centre *5 isin the S configuration;

*AA14*

R⁶ is C₁₋₆ alkyl optionally substituted with one or more substituents;chiral centre *6 is in the S configuration or the R configuration;

*AA15*

Is Ala and is joined to *AA9* via *L2* wherein *L2* attaches to themethyl side chain;

*AA16*

R^(C) is OH or NH₂; R⁸ is selected from the group consisting of C₆₋₁₀aryl, 5- to 10-membered heteroaryl, —C₁₋₆alkylene(C₆₋₁₀ aryl) and—C₁₋₆alkylene(5- to 10-membered heteroaryl), wherein the C₆₋₁₀ aryl andthe C₆₋₁₀ aryl of —C₁₋₆alkylene(C₆₋₁₀ aryl) and the 5- to 10-memberedheteroaryl and the 5- to 10-membered heteroaryl of —C₁₋₆ alkylene(5- to10-membered heteroaryl) are optionally substituted with one or moresubstituents, and wherein the C₁₋₆alkylene of —C₁₋₆ alkylene(C₆₋₁₀ aryl)and —C₁₋₆alkylene(5- to 10-membered heteroaryl) is optionallysubstituted with one or more substituents; chiral centre *8 is in the Sconfiguration or the R configuration,

*L2*

L is selected from the group consisting of:

wherein X is S or O; and vii)

provided that:

when L is

R⁴ is —CH₂-(phenylene)-N(H)C(O)NH₂; R³ is —CH₂-(phenyl) or—CH₂-(phenylene)-N(H)C(O)R³⁵, wherein the phenyl of —CH₂-(phenyl) issubstituted with hydroxy and wherein R³⁵ is2,6-dioxohexahydropyrimidine; R⁵ is NH₂; n¹ is 4; R¹² is H; R⁶ is—CH(OH)(CH₃); and R⁸ is —CH₂-(phenyl) or —CH₂-(napthyl), wherein thephenyl is substituted with hydroxy, then R¹ is not —CH₂-(phenyl),wherein the phenyl is substituted with —Cl or —NO₂.

Although various embodiments of the invention are disclosed herein, manyadaptations and modifications may be made within the scope of theinvention in accordance with the common general knowledge of thoseskilled in this art. Such modifications include the substitution ofknown equivalents for any aspect of the invention in order to achievethe same result in substantially the same way. Numeric ranges areinclusive of the numbers defining the range. The word “comprising” isused herein as an open-ended term, substantially equivalent to thephrase “including, but not limited to”, and the word “comprises” has acorresponding meaning. As used herein, the singular forms “a”, “an” and“the” include plural referents unless the context clearly dictatesotherwise. Thus, for example, reference to “a thing” includes more thanone such thing. Citation of references herein is not an admission thatsuch references are prior art to the present invention. Any prioritydocument(s) and all publications, including but not limited to patentsand patent applications, cited in this specification are incorporatedherein by reference as if each individual publication were specificallyand individually indicated to be incorporated by reference herein and asthough fully set forth herein. The invention includes all embodimentsand variations substantially as hereinbefore described and withreference to the examples and drawings.

What is claimed is:
 1. A compound having the structure of Formula I:

or a salt thereof, wherein: R^(C) is OH or NHR¹⁶, wherein R¹⁶ is H orC₁₋₆ alkyl optionally substituted with one or more substituents; R^(N)is selected from the group consisting of: (i) H; (ii) C₁₋₆alkyl; (iii)—C(O)R¹⁷, wherein R¹⁷ is selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally substituted with one or more substituents, andwherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionallysubstituted with one or more substituents; (iv) —C(O)C₁₋₆alkylene-C(O)OR¹⁸, wherein R¹⁸ is H or C₁₋₆alkyl optionally substitutedwith one or more substituents; (v) —C(O)C₁₋₆ alkylene-N(R²⁰)C(O)R¹⁹,wherein R¹⁹ is selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀aryl, and 5- to 10-membered heteroaryl, wherein the C₁₋₆alkyl isoptionally substituted with one or more substituents, and wherein theC₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally substitutedwith one or more substituents, and wherein R²⁰ is H or C₁₋₆ alkyl; (vi)—C(O)C₁₋₆ alkylene-NR²¹R²², wherein each of R²¹ and R²² is independentlyselected from the group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5-to 10-membered heteroaryl, wherein the C₁₋₆alkyl is optionallysubstituted with one or more substituents, and wherein the C₆₋₁₀ aryland 5- to 10-membered heteroaryl are optionally substituted with one ormore substituents; (vii) —C(O)C₁₋₆ alkylene-C(O)NR²³R²⁴, wherein each ofR²³ and R²⁴ is independently selected from the group consisting of H,C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein theC₁₋₆alkyl is optionally substituted with one or more substituents, andwherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionallysubstituted with one or more substituents; (viii) —C(O)C₁₋₆alkylene-S(O)₂R²⁵, wherein R²⁵ is selected from the group consisting ofC₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein theC₁₋₆alkyl is optionally substituted with one or more substituents, andwherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionallysubstituted with one or more substituents; and (ix) —S(O)₂R²⁶, whereinR²⁶ is selected from the group consisting of C₁₋₆ alkyl, C₆₋₁₀ aryl, and5- to 10-membered heteroaryl, wherein the C₁₋₆alkyl is optionallysubstituted with one or more substituents, and wherein the C₆₋₁₀ aryland 5- to 10-membered heteroaryl are optionally substituted with one ormore substituents; R¹ is selected from the group consisting ofC₁₋₆alkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, —C₁₋₆alkylene(C₆₋₁₀ aryl) and —C₁₋₆alkylene(5- to 10-membered heteroaryl),wherein the C₁₋₆alkyl, the C₆₋₁₀ aryl, the C₆₋₁₀ aryl of—C₁₋₆alkylene(C₆₋₁₀ aryl), the 5- to 10-membered heteroaryl and the 5-to 10-membered heteroaryl of —C₁₋₆alkylene(5- to 10-membered heteroaryl)are optionally substituted with one or more substituents, and whereinthe C₁₋₆alkylene of —C₁₋₆alkylene(C₆₋₁₀ aryl) and —C₁₋₆ alkylene(5- to10-membered heteroaryl) is optionally substituted with one or moresubstituents; R³ is selected from the group consisting of: (i) C₆₋₁₀aryl which is optionally substituted with one or more substituents; (ii)5- to 10-membered heteroaryl which is optionally substituted with one ormore substituents; (iii) —C₁₋₆alkylene(C₆₋₁₀ aryl), wherein the C₆₋₁₀aryl is optionally substituted with one or more substituents, andwherein the C₁₋₆ alkylene is optionally substituted with one or moresubstituents; (iv) —C₁₋₆alkylene(5- to 10-membered heteroaryl), whereinthe 5- to 10-membered heteroaryl is optionally substituted with one ormore substituents, and wherein the C₁₋₆ alkylene is optionallysubstituted with one or more substituents; (v) —C₁₋₆alkylene-NR²⁷C(O)R²⁸, wherein: R²⁷ is H or C₁₋₆alkyl; R²⁸ is selectedfrom the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, 5- to 10-memberedheteroaryl, and —NR²⁹R³⁰, wherein the C₁₋₆alkyl is optionallysubstituted with one or more substituents, and wherein the C₆₋₁₀ aryland 5- to 10-membered heteroaryl are optionally substituted with one ormore substituents; and wherein each of R²⁹ and R³⁰ is independentlyselected from the group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5-to 10-membered heteroaryl, wherein the C₁₋₆alkyl is optionallysubstituted with one or more substituents, and wherein the C₆₋₁₀ aryland 5- to 10-membered heteroaryl are optionally substituted with one ormore substituents; (vi) —(C₆₋₁₀ arylene)-C(O)NR³¹R¹¹ or —C₁₋₆alkylene-(C₆₋₁₀ arylene)-C(O)NR³¹R¹¹, wherein each of R³¹ and R¹¹ isindependently selected from the group consisting of H, C₁₋₆ alkyl, C₆₋₁₀aryl, and 5- to 10-membered heteroaryl, wherein the C₁₋₆ alkyl isoptionally substituted with one or more substituents, and wherein theC₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally substitutedwith one or more substituents; (vii) —(C₆₋₁₀ arylene)-NR³³R³⁴ or —C₁₋₆alkylene-(C₆₋₁₀ arylene)-NR³³R³⁴, wherein: each of R³³ and R³⁴ isindependently selected from the group consisting of H, C₁₋₆ alkyl, C₆₋₁₀aryl, 5- to 10-membered heteroaryl, —C(O)R³⁵, —C(O)NR³⁶R³⁷, and —SO₂R³⁸,wherein the C₁₋₆alkyl is optionally substituted with one or moresubstituents, and wherein the C₆₋₁₀ aryl and 5- to 10-memberedheteroaryl are optionally substituted with one or more substituents; R³⁵is selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, 5- to10-membered heteroaryl, and 5- to 10-membered heterocycloalkyl, whereinthe C₁₋₆alkyl is optionally substituted with one or more substituents,and wherein the C₆₋₁₀ aryl, 5-to 10-membered heteroaryl, and 5- to10-membered heterocycloalkyl are optionally substituted with one or moresubstituents; each of R³⁶ and R³⁷ is independently selected from thegroup consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl, wherein the C₁₋₆alkyl is optionally substituted with one ormore substituents, and wherein the C₆₋₁₀ aryl and 5- to 10-memberedheteroaryl are optionally substituted with one or more substituents; andR³⁸ is selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and5- to 10-membered heteroaryl, wherein the C₁₋₆alkyl is optionallysubstituted with one or more substituents, and wherein the C₆₋₁₀ aryland 5- to 10-membered heteroaryl are optionally substituted with one ormore substituents; (viii) —(C₆₋₁₀ arylene)-SO₂NR³⁹R⁴⁰ or —C₁₋₆alkylene-(C₆₋₁₀ arylene)-SO₂NR³⁹R⁴⁰, wherein each of R³⁹ and R⁴⁰ isindependently selected from the group consisting of H, C₁₋₆ alkyl, C₆₋₁₀aryl, and 5- to 10-membered heteroaryl, wherein the C₁₋₆ alkyl isoptionally substituted with one or more substituents, and wherein theC₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally substitutedwith one or more substituents; (ix) —(C₆₋₁₀ arylene)-(C₁₋₆alkylene)-NR⁴¹R⁴² or —C₁₋₆ alkylene-(C₆₋₁₀ arylene)-(C₁₋₆alkylene)-NR⁴¹R⁴², wherein: each of R⁴¹ and R⁴² is independentlyselected from the group consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, 5- to10-membered heteroaryl, —C(O)R⁴³, and —C(O)NR⁴⁴R⁴⁵, wherein theC₁₋₆alkyl is optionally substituted with one or more substituents, andwherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionallysubstituted with one or more substituents; R⁴³ is selected from thegroup consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl, wherein the C₁₋₆alkyl is optionally substituted with one ormore substituents, and wherein the C₆₋₁₀ aryl and 5- to 10-memberedheteroaryl are optionally substituted with one or more substituents; andeach of R⁴⁴ and R⁴⁵ is independently selected from the group consistingof H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, whereinthe C₁₋₆alkyl is optionally substituted with one or more substituents,and wherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl areoptionally substituted with one or more substituents; (x) —(C₆₋₁₀arylene)-OR⁴⁶ or —C₁₋₆ alkylene-(C₆₋₁₀ arylene)-OR⁴⁶, wherein R⁴⁶ isselected from the group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5-to10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally substitutedwith one or more substituents, and wherein the C₆₋₁₀ aryl and 5- to10-membered heteroaryl are optionally substituted with one or moresubstituents; and (xi) —C₁₋₆ alkylene-(C₆₋₁₀arylene)-N(R⁴⁷)—C(O)—CHR⁴⁸—NR⁴⁹R⁵⁰, wherein R⁴⁷ is H or CH₃, R⁴⁸ is H orC₁₋₆alkyl optionally substituted with one or more substituents eachindependently selected from the group consisting of hydroxyl, —COOH,—NH₂, —C(O)NH₂, and —N(H)C(O)NH₂, and each of R⁴⁹ and R⁵⁰ isindependently H, CH₃ or acetyl; R⁴ is selected from the group consistingof: (i) —C₁₋₆ alkylene-N(R⁵³)C(O)NR⁵¹R⁵², wherein each of R⁵¹ and R⁵² isindependently selected from the group consisting of H, C₁₋₆alkyl, C₆₋₁₀aryl, and 5- to 10-membered heteroaryl, wherein the C₁₋₆alkyl isoptionally substituted with one or more substituents, and wherein theC₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally substitutedwith one or more substituents, and wherein R⁵³ is H or C₁₋₆ alkyl; (ii)—C₁₋₆ alkylene-N(R⁵⁵)C(O)R⁵⁴, wherein R⁵⁴ is selected from the groupconsisting of C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl,wherein the C₁₋₆ alkyl is optionally substituted with one or moresubstituents, and wherein the C₆₋₁₀ aryl and 5- to 10-memberedheteroaryl are optionally substituted with one or more substituents, andwherein R⁵⁵ is H or C₁₋₆ alkyl; (iii) —(C₆₋₁₀ arylene)-C(O)NR⁵⁶R⁵⁷ or—C₁₋₆ alkylene-(C₆₋₁₀ arylene)-C(O)NR⁵⁶R⁵⁷, wherein each of R⁵⁶ and R⁵⁷is independently selected from the group consisting of H, C₁₋₆ alkyl,C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the C₁₋₆ alkyl isoptionally substituted with one or more substituents, and wherein theC₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally substitutedwith one or more substituents; (iv) —(C₆₋₁₀ arylene)-N(R⁵⁹)C(O)R⁵⁸ or—C₁₋₆ alkylene-(C₆₋₁₀ arylene)-N(R⁵⁹)C(O)R⁵⁸, wherein R⁵⁸ is selectedfrom the group consisting of C₁₋₆ alkyl, C₆₋₁₀ aryl, 5- to 10-memberedheteroaryl, and 5- to 10-membered heterocycloalkyl, wherein theC₁₋₆alkyl is optionally substituted with one or more substituents, andwherein the C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, and 5- to10-membered heterocycloalkyl are optionally substituted with one or moresubstituents, and wherein R⁵⁹ is H or C₁₋₆ alkyl; (v) —(C₆₋₁₀arylene)-N(R⁶²)C(O)NR⁶⁰R⁶¹ or —C₁₋₆ alkylene-(C₆₋₁₀arylene)-N(R⁶²)C(O)NR⁶⁰R⁶¹, wherein each of R⁶⁰ and R⁶¹ is independentlyselected from the group consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5-to 10-membered heteroaryl, wherein the C₁₋₆alkyl is optionallysubstituted with one or more substituents, and wherein the C₆₋₁₀ aryland 5- to 10-membered heteroaryl are optionally substituted with one ormore substituents, and wherein R⁶² is H or C₁₋₆ alkyl; (vi) —(C₆₋₁₀arylene)-N(R⁶⁴)SO₂R⁶³ or —C₁₋₆ alkylene-(C₆₋₁₀ arylene)-N(R⁶⁴)SO₂R⁶³,wherein R⁶³ is selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀aryl, and 5- to 10-membered heteroaryl, wherein the C₁₋₆alkyl isoptionally substituted with one or more substituents, and wherein theC₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionally substitutedwith one or more substituents, and wherein R⁶⁴ is H or C₁₋₆ alkyl; (vii)—(C₆₋₁₀ arylene)-SO₂NR⁶⁵R⁶⁶ or —C₁₋₆ alkylene-(C₆₋₁₀arylene)-SO₂NR⁶⁵R⁶⁶, wherein each of R⁶⁵ and R⁶⁶ is independentlyselected from the group consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5-to 10-membered heteroaryl, wherein the C₁₋₆ alkyl is optionallysubstituted with one or more substituents, and wherein the C₆₋₁₀ aryland 5- to 10-membered heteroaryl are optionally substituted with one ormore substituents; (viii) —(C₆₋₁₀ arylene)-(C₁₋₆ alkylene)-NR⁶⁷R⁶⁸ or—C₁₋₆ alkylene-(C₆₋₁₀ arylene)-(C₁₋₆ alkylene)-NR⁶⁷R⁶⁸, wherein: each ofR⁶⁷ and R⁶⁸ is independently selected from the group consisting of H,C₁₋₆ alkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, —C(O)R⁶⁹, and—C(O)NR⁷⁰R⁷¹, wherein the C₁₋₆alkyl is optionally substituted with oneor more substituents, and wherein the C₆₋₁₀ aryl and 5- to 10-memberedheteroaryl are optionally substituted with one or more substituents; R⁶⁹is selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and 5-to 10-membered heteroaryl, wherein the C₁₋₆alkyl is optionallysubstituted with one or more substituents, and wherein the C₆₋₁₀ aryland 5- to 10-membered heteroaryl are optionally substituted with one ormore substituents; and each of R⁷⁰ and R⁷¹ is independently selectedfrom the group consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to10-membered heteroaryl, wherein the C₁₋₆alkyl is optionally substitutedwith one or more substituents, and wherein the C₆₋₁₀ aryl and 5- to10-membered heteroaryl are optionally substituted with one or moresubstituents; (ix) —(C₆₋₁₀ arylene)-NR⁷²R⁷³ or —C₁₋₆ alkylene-(C₆₋₁₀arylene)-NR⁷²R⁷³, wherein each of R⁷² and R⁷³ is independently selectedfrom the group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to10-membered heteroaryl, wherein the C₁₋₆ alkyl is optionally substitutedwith one or more substituents, and wherein the C₆₋₁₀ aryl and 5- to10-membered heteroaryl are optionally substituted with one or moresubstituents; (x) —(C₆₋₁₀ arylene)-OR⁷⁴ or —C₁₋₆ alkylene-(C₆₋₁₀arylene)-OR⁷⁴, wherein R⁷⁴ is selected from the group consisting of H,C₁₋₆alkyl, C₆₋₁₀ aryl, and 5-to 10-membered heteroaryl, wherein theC₁₋₆alkyl is optionally substituted with one or more substituents, andwherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl are optionallysubstituted with one or more substituents; (xi) —C₁₋₆ alkylene-(C₆₋₁₀arylene)-N(R⁷⁵)—C(O)—CHR⁷⁶—NR⁷⁷R⁷⁸, wherein R⁷⁵ is H or CH₃, R⁷⁶ is H orC₁₋₆alkyl optionally substituted with one or more substituents eachindependently selected from the group consisting of hydroxyl, —COOH,—NH₂, —C(O)NH₂, and —N(H)C(O)NH₂, and each of R⁷⁷ and R⁷⁸ isindependently H, CH₃ or acetyl; and (xii) —C₁₋₆ alkylene-(C₆₋₁₀arylene)-CN; R⁵ is selected from the group consisting of: (i) —NR⁷⁹R⁸⁰,wherein each of R⁷⁹ and R⁸⁰ is independently selected from the groupconsisting of H, C₁₋₆ alkyl, —C(O)R⁸¹, and —C(═NR⁸²)NR⁸³R⁸⁴, or R⁷⁹ andR⁸⁰, together with the N atom to which they are attached, form 5- to10-membered heteroaryl or 5- to 10-membered heterocycloalkyl, whereinthe C₁₋₆ alkyl is optionally substituted with one or more substituents,and wherein the 5- to 10-membered heteroaryl and 5- to 10-memberedheterocycloalkyl are optionally substituted with one or moresubstituents, R⁸¹ is selected from the group consisting of H, —NH₂,C₁₋₁₆ alkyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl; and each of R⁸², R⁸³, and R⁸⁴ is independently selected fromthe group consisting of H, C₁₋₁₆₋alkyl, C₁₋₆ haloalkyl, C₆₋₁₀ aryl, and5- to 10-membered heteroaryl; and (ii) —N⁺R⁸⁵R⁸⁶R⁸⁷, wherein each ofR⁸⁵, R⁸⁶, and R⁸⁷ is independently C₁₋₆ alkyl; n¹ is 1, 2, 3, 4, 5, or6; R⁶ is C₁₋₆ alkyl optionally substituted with one or moresubstituents; R⁸ is selected from the group consisting of C₁₋₆alkyl,C₆₋₁₀ aryl, 5- to 10-membered heteroaryl, —C₁₋₆ alkylene(C₆₋₁₀ aryl) and—C₁₋₆alkylene(5- to 10-membered heteroaryl), wherein the C₁₋₆alkyl, theC₆₋₁₀ aryl, the C₆₋₁₀ aryl of —C₁₋₆alkylene(C₆₋₁₀ aryl), the 5- to10-membered heteroaryl and the 5- to 10-membered heteroaryl of—C₁₋₆alkylene(5- to 10-membered heteroaryl) are optionally substitutedwith one or more substituents, and wherein the C₁₋₆alkylene of—C₁₋₆alkylene(C₆₋₁₀ aryl) and —C₁₋₆ alkylene(5- to 10-memberedheteroaryl) is optionally substituted with one or more substituents; R⁹is H or C₁₋₆ alkyl; R¹⁰ is H or C₁₋₆ alkyl; R¹¹ is H or C₁₋₆ alkyl; R¹²is H or C₁₋₆ alkyl; R¹³ is H or C₁₋₆ alkyl; R¹⁴ is H or C₁₋₆ alkyl; R¹⁵is H or C₁₋₆ alkyl; and L is selected from the group consisting of:

wherein X is S or O; and

chiral centre *1 is in the S configuration or the R configuration;chiral centre *2 is in the S configuration or the R configuration;chiral centre *3 is in the S configuration or the R configuration;chiral centre *4 is in the S configuration or the R configuration;chiral centre *5 is in the S configuration or the R configuration;chiral centre *6 is in the S configuration or the R configuration;chiral centre *7 is in the S configuration or the R configuration; andchiral centre *8 is in the S configuration or the R configuration,provided that: i) when R^(C) is NH₂, R^(N) is H or —C(O)CH₂N₃, R¹ is

R³ is

R⁵ is NH₂, n¹ is 4, R⁶ is CH(OH)(CH₃), R⁸ is

each of R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴ and R¹⁵ is H, and L is

then R⁴ is not

and ii) when R^(C) is NH₂, R^(N) is H, R¹ is

R⁵ is NH₂, n¹ is 4, R⁶ is —CH(CH₃)₂, R⁸ is —CH(OH)(CH₃), each of R⁹,R¹⁰, R¹¹, R¹², R¹³, R¹⁴ and R¹⁵ is H, and L is

then R is not


2. The compound or salt of claim 1, wherein R⁴ is selected from thegroup consisting of: (i) —C₁₋₆ alkylene-N(R⁵³)C(O)NR⁵¹R⁵², wherein eachof R⁵¹ and R⁵² is independently selected from the group consisting of H,C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, and wherein R⁵³is H or C₁₋₆alkyl; (ii) —C₁₋₆ alkylene-(C₆₋₁₀ arylene)-C(O)NR⁵⁶R⁵⁷,wherein each of R⁵⁶ and R⁵⁷ is independently selected from the groupconsisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl, wherein the C₁₋₆alkyl is optionally substituted with one ormore substituents, and wherein the C₆₋₁₀ aryl and 5- to 10-memberedheteroaryl are optionally substituted with one or more substituents;(iii) —C₁₋₆ alkylene-(C₆₋₁₀ arylene)-N(R⁵⁹)C(O)R⁵⁸, wherein R⁵⁸ isselected from the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to10-membered heteroaryl, and wherein R⁵⁹ is H or C₁₋₆alkyl; (iv) —C₁₋₆alkylene-(C₆₋₁₀ arylene)-N(R⁶²)C(O)NR⁶⁰R⁶¹, wherein R⁶⁰ is selected fromthe group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl, R⁶¹ is selected from the group consisting of C₁₋₆ alkyl,C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, wherein the C₁₋₆alkyl ofR⁶⁰ or R⁶¹ is optionally substituted with one or more substituents, andwherein the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl of R⁶⁰ or R⁶¹are optionally substituted with one or more substituents, and whereinR⁶² is H or C₁₋₆alkyl; (v) —C₁₋₆ alkylene-(C₆₋₁₀ arylene)-N(R⁶⁴)SO₂R⁶³,wherein R⁶³ is selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀aryl, and 5- to 10-membered heteroaryl, and wherein R⁶⁴ is H or C₁₋₆alkyl; (vi) —C₁₋₆ alkylene-(C₆₋₁₀ arylene)-(C₁₋₆ alkylene)-NR⁶⁷R⁶⁸,wherein: each of R⁶⁷ and R⁶⁸ is independently selected from the groupconsisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, 5- to 10-membered heteroaryl,—C(O)R⁶⁹, and —C(O)NR⁷⁰R⁷¹; R⁶⁹ is selected from the group consisting ofC₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl; and each of R⁷⁰and R⁷¹ is independently selected from the group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl; (vii) —C₁₋₆alkylene-(C₆₋₁₀ arylene)-NR⁷²R⁷³, wherein each of R⁷² and R⁷³ isindependently selected from the group consisting of H, C₁₋₆alkyl, C₆₋₁₀aryl, and 5- to 10-membered heteroaryl; and (viii) —C₁₋₆ alkylene-(C₆₋₁₀arylene)-CN.
 3. The compound or salt of claim 1, wherein R⁴ is selectedfrom the group consisting of: (i) —C₃₋₄ alkylene-N(R⁵³)C(O)NR⁵¹R⁵²,wherein each of R⁵¹ and R⁵² is independently selected from the groupconsisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl, and wherein R⁵³ is H or C₁₋₆alkyl; (ii) —C₁₋₂ alkylene-(C₆arylene)-C(O)NR⁵⁶R⁵⁷, wherein each of R⁵⁶ and R⁵⁷ is independentlyselected from the group consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5-to 10-membered heteroaryl, wherein the C₁₋₆alkyl is optionallysubstituted with one or more substituents, and wherein the C₆₋₁₀ aryland 5- to 10-membered heteroaryl are optionally substituted with one ormore substituents; (iii) —C₁₋₂ alkylene-(C₆ arylene)-N(R⁵⁹)C(O)R⁵⁸,wherein R⁵⁸ is selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀aryl, and 5- to 10-membered heteroaryl, and wherein R⁵⁹ is H orC₁₋₆alkyl; (iv) —C₁₋₂ alkylene-(C₆ arylene)-N(R⁶²)C(O)NR⁶⁰R⁶¹, whereinR⁶⁰ is selected from the group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl,and 5- to 10-membered heteroaryl, R⁶¹ is selected from the groupconsisting of C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl,wherein the C₁₋₆alkyl of R⁶⁰ or R⁶¹ is optionally substituted with oneor more substituents, and wherein the C₆₋₁₀ aryl and 5- to 10-memberedheteroaryl of R⁶⁰ or R⁶¹ are optionally substituted with one or moresubstituents, and wherein R⁶² is H or C₁₋₆alkyl; (v) —C₁₋₂ alkylene-(C₆arylene)-N(R⁶⁴)SO₂R⁶³, wherein R⁶³ is selected from the group consistingof C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, and whereinR⁶⁴ is H or C₁₋₆alkyl; (vi) —C₁₋₂ alkylene-(C₆ arylene)-(C₁₋₂alkylene)-NR⁶⁷R⁶⁸, wherein: each of R⁶⁷ and R⁶⁸ is independentlyselected from the group consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, 5- to10-membered heteroaryl, —C(O)R⁶⁹, and —C(O)NR⁷⁰R⁷¹; R⁶⁹ is selected fromthe group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl; and each of R⁷⁰ and R⁷¹ is independently selected from thegroup consisting of H, C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl; (vii) —C₁₋₂ alkylene-(C₆ arylene)-NR⁷²R⁷³, wherein each ofR⁷² and R⁷³ is independently selected from the group consisting of H,C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl; and (viii)—C₁₋₂ alkylene-(C₆ arylene)-CN.
 4. The compound or salt of claim 1,wherein R⁴ is selected from the group consisting of —C₃₋₄alkylene-N(R⁵³)C(O)NR⁵¹R⁵², —C₁₋₂ alkylene-(C₆ arylene)-C(O)NR⁵⁶R⁵⁷,—C₁₋₂ alkylene-(C₆ arylene)-N(R⁵⁹)C(O)R⁵⁸, —C₁₋₂ alkylene-(C₆arylene)-N(R⁶²)C(O)NR⁶⁰R⁶¹, —C₁₋₂ alkylene-(C₆ arylene)-N(R⁶⁴)SO₂R⁶³,—C₁₋₂ alkylene-(C₆ arylene)-(C₁₋₂ alkylene)-NR⁶⁷R⁶⁸, —C₁₋₂ alkylene-(C₆arylene)-NR⁷²R⁷³, and —C₁₋₂ alkylene-(C₆ arylene)-CN, wherein each ofR⁵¹, R⁵², R⁵³, R⁵⁶, R⁵⁷, R⁵⁹, R⁶⁰, R⁶² and R⁶⁴ is H, each of R⁵⁸ and R⁶³is independently C₆₋₁₀ aryl, R⁶¹ is C₆₋₁₀ aryl which is optionallysubstituted with C₁₋₃ alkoxy, each of R⁶⁷ and R⁶⁸ is independentlyselected from the group consisting of H, —C(O)R⁶⁹, and —C(O)NR⁷⁰R⁷¹,wherein R⁶⁹ is C₁₋₆alkyl and each of R⁷⁰ and R⁷¹ is H, and each of R⁷²and R⁷³ is independently selected from the group consisting of H andC₁₋₆alkyl.
 5. The compound or salt of claim 1, wherein R⁴ is —C₁₋₆alkylene-(C₆₋₁₀ arylene)-C(O)NR⁵⁶R⁵⁷ or —C₁₋₆ alkylene-(C₆₋₁₀arylene)-N(R⁶²)C(O)NR⁶⁰R⁶¹, wherein each of R⁵⁶ and R⁵⁷ is independentlyselected from the group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5-to 10-membered heteroaryl, R⁶⁰ is selected from the group consisting ofH, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, R⁶¹ isselected from the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to10-membered heteroaryl, and R⁶² is H or C₁₋₆alkyl, wherein the C₁₋₆alkylof R⁵⁶, R⁵⁷, R⁶⁰ or R⁶¹ is optionally substituted with one or moresubstituents, and the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl ofR⁵⁶, R⁵⁷, R⁶⁰ or R⁶¹ are optionally substituted with one or moresubstituents.
 6. The compound or salt of claim 5, wherein R⁴ is —C₁₋₂alkylene-(C₆ arylene)-C(O)NR⁵⁶R⁵⁷ or —C₁₋₂ alkylene-(C₆arylene)-N(R⁶²)C(O)NR⁶⁰R⁶¹, wherein each of R⁵⁶ and R⁵⁷ is independentlyselected from the group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5-to 10-membered heteroaryl, R⁶⁰ is selected from the group consisting ofH, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl, R⁶¹ isselected from the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to10-membered heteroaryl, and R⁶² is H or C₁₋₆alkyl, wherein the C₁₋₆alkyl of R⁵⁶, R⁵⁷, R⁶⁰ or R⁶¹ is optionally substituted with one or moresubstituents, and the C₆₋₁₀ aryl and 5- to 10-membered heteroaryl ofR⁵⁶, R⁵⁷, R⁶⁰ or R⁶¹ are optionally substituted with one or moresubstituents.
 7. The compound or salt of claim 6, wherein R⁴ is

wherein each of R¹⁰¹ and R¹⁰² is independently selected from the groupconsisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryland R¹¹⁸ is selected from the group consisting of H, halogen, hydroxy,—NO₂, and C₁₋₆alkoxy.
 8. The compound or salt of claim 1, wherein R⁴ is


9. The compound or salt of claim 8, wherein R⁴ is


10. The compound or salt of claim 1, wherein R⁴ is —C₃₋₄alkylene-N(R⁵³)C(O)NR⁵¹R⁵², R⁵³ is H, and each of R⁵¹ and R⁵² is H. 11.The compound or salt of claim 1, wherein R⁴ is —C₁ alkylene-(C₆arylene)-N(R⁵⁹)C(O)R⁵⁸, R⁵⁹ is H, and R⁵⁸ is phenyl.
 12. The compound orsalt of claim 1, wherein R⁴ is —C₁ alkylene-(C₆ arylene)-N(R⁶⁴)SO₂R⁶³,R⁶⁴ is H, and R⁶³ is phenyl.
 13. The compound or salt of claim 1,wherein R⁴ is —C₁ alkylene-(C₆ arylene)-(C₁ alkylene)-NR⁶⁷R⁶⁸, whereineach of R⁶⁷ and R⁶⁸ is H or wherein R⁶⁷ is H, R⁶⁸ is —C(O)NR⁷⁰R⁷¹, andeach of R⁷⁰ and R⁷¹ is H.
 14. The compound or salt of claim 1, whereinR⁴ is —C₁ alkylene-(C₆ arylene)-NR⁷²R⁷³ and R⁷² is H and R⁷³ isC₁₋₆alkyl.
 15. The compound or salt of claim 1, wherein R⁴ is —C₁alkylene-(C₆ arylene)-CN.
 16. The compound or salt of claim 1, whereinR⁵ is —NR⁷⁹R⁸⁰ and each of R⁷⁹ and R⁸⁰ is independently selected fromthe group consisting of H, C₁₋₆ alkyl, —C(O)R⁸¹, and —C(═NR⁸²)NR⁸³R⁸⁴,wherein R⁸¹ is C₁₋₆ alkyl and each of R⁸², R⁸³, and R⁸⁴ is H.
 17. Thecompound or salt of claim 16, wherein R⁵ is —NR⁷⁹R⁸⁰ and each of R⁷⁹ andR⁸⁰ is independently selected from the group consisting of H andC₁₋₆alkyl.
 18. The compound or salt of claim 17, wherein R⁵ is —NH₂,—NHCH₃ or —N(CH₃)₂.
 19. The compound or salt of claim 18, wherein R⁵ is—NH₂.
 20. The compound or salt of claim 18, wherein R⁵ is —NHCH₃. 21.The compound or salt of claim 18, wherein R⁵ is —N(CH₃)₂.
 22. Thecompound or salt of claim 1, wherein n¹ is 3 or
 4. 23. The compound orsalt of claim 22, wherein n¹ is
 4. 24. The compound or salt of claim 1,wherein R^(C) is OH or NH₂.
 25. The compound or salt of claim 24,wherein R^(C) is NH₂.
 26. The compound or salt of claim 1, wherein R^(N)is selected from the group consisting of: (i) H; (ii) C₁₋₆alkyl; (iii)—C(O)R¹⁷, wherein R¹⁷ is selected from the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl; (iv) —C(O)C₁₋₆alkylene-C(O)OR¹⁸, wherein R¹⁸ is H or C₁₋₆alkyl; (v) —C(O)C₁₋₆alkylene-N(R²⁰)C(O)R¹⁹, wherein R¹⁹ is selected from the groupconsisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl,and wherein R²⁰ is H or C₁₋₆alkyl; (vi) —C(O)C₁₋₆ alkylene-NR²¹R²²,wherein each of R²¹ and R²² is independently selected from the groupconsisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl; (vii) —C(O)C₁₋₆ alkylene-C(O)NR²³R²⁴, wherein each of R²³and R²⁴ is independently selected from the group consisting of H,C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl; (viii)—C(O)C₁₋₆ alkylene-S(O)₂R²⁵, wherein R²⁵ is selected from the groupconsisting of C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl;and (ix) —S(O)₂R²⁶, wherein R²⁶ is selected from the group consisting ofC₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl.
 27. Thecompound or salt of claim 26, wherein R^(N) is selected from the groupconsisting of: (i) H; (ii) C₁₋₆alkyl; (iii) —C(O)R¹⁷, wherein R¹⁷ isselected from the group consisting of C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to10-membered heteroaryl; (iv) —C(O)C₁₋₃ alkylene-C(O)OR¹⁸, wherein R¹⁸ isH or C₁₋₆alkyl; (v) —C(O)C₁₋₃ alkylene-N(R²⁰)C(O)R¹⁹, wherein R¹⁹ isselected from the group consisting of C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to10-membered heteroaryl, and wherein R²⁰ is H or C₁₋₆alkyl; (vi)—C(O)C₁₋₃ alkylene-NR²¹R²², wherein each of R²¹ and R²² is independentlyselected from the group consisting of H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5-to 10-membered heteroaryl; (vii) —C(O)C₁₋₃ alkylene-C(O)NR²³R²⁴, whereineach of R²³ and R²⁴ is independently selected from the group consistingof H, C₁₋₆alkyl, C₆₋₁₀ aryl, and 5- to 10-membered heteroaryl; and(viii) —C(O)C₁₋₃ alkylene-S(O)₂R²⁵, wherein R²⁵ is selected from thegroup consisting of C₁₋₆ alkyl, C₆₋₁₀ aryl, and 5- to 10-memberedheteroaryl.
 28. The compound or salt of claim 26, wherein R^(N) isselected from the group consisting of H, C₁₋₆ alkyl, —C(O)R¹⁷, —C(O)C₁₋₆alkylene-C(O)OR¹⁸, —C(O)C₁₋₆ alkylene-N(R²⁰)C(O)R¹⁹, —C(O)C₁₋₆alkylene-NR²¹R²², —C(O)C₁₋₆ alkylene-C(O)NR²³R²⁴, and —C(O)C₁₋₆alkylene-S(O)₂R²⁵, wherein R¹⁷ is C₁₋₆ alkyl or 5- to 6-memberedheteroaryl, R¹⁸ is C₁₋₆ alkyl, R¹⁹ is C₁₋₆ alkyl or C₆ aryl, each ofR²⁰, R²¹, R²², R²³ and R²⁴ is H, and R²⁵ is C₆ aryl.
 29. The compound orsalt of claim 28, wherein R^(N) is selected from the group consisting ofH, C₁₋₃ alkyl, —C(O)R¹⁷, —C(O)C₁₋₃ alkylene-C(O)OR¹⁸, —C(O)C₁₋₃alkylene-N(R²⁰)C(O)R¹⁹, —C(O)C₁₋₃ alkylene-NR²¹R²², —C(O)C₁₋₃alkylene-C(O)NR²³R²⁴, and —C(O)C₁₋₃ alkylene-S(O)₂R²⁵, wherein R¹⁷ isC₁₋₆ alkyl or 5- to 6-membered heteroaryl, R¹⁸ is C₁₋₃ alkyl, R¹⁹ isC₁₋₃ alkyl or C₆ aryl, each of R²⁰, R²¹, R²², R²³ and R²⁴ is H, and R²⁵is C₆ aryl.
 30. The compound or salt of claim 29, wherein R^(N) is H.31. The compound or salt of claim 1, wherein R¹ is —C₁₋₃ alkylene(C₆₋₁₀aryl), wherein the C₆₋₁₀ aryl is optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen, hydroxy, —NO₂, and C₁₋₆ alkoxy.
 32. The compound or salt ofclaim 31, wherein R¹ is —C₁₋₂ alkylene(C₆ aryl), wherein the C₆ aryl isoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, hydroxyl, —NO₂, and C₁₋₆alkoxy.
 33. The compound or salt of claim 32, wherein R¹ is

wherein R⁸⁸ is H, halogen, hydroxyl or C₁₋₃ alkoxy.
 34. The compound orsalt of claim 33, wherein R⁸⁸ is Cl.
 35. The compound or salt of claim1, wherein R³ is —C₁₋₃ alkylene(C₆₋₁₀ aryl), wherein the C₆₋₁₀ aryl isoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, hydroxy, —NO₂, and C₁₋₆alkoxy.
 36. The compound or salt of claim 35, wherein R³ is —C₁₋₂alkylene(C₆ aryl), wherein the C₆ aryl is optionally substituted withone or more substituents each independently selected from the groupconsisting of halogen, hydroxyl, —NO₂, and C₁₋₆ alkoxy.
 37. The compoundor salt of claim 36, wherein R³ is

wherein R⁸⁹ is H, halogen, hydroxyl or C₁₋₃ alkoxy.
 38. The compound orsalt of claim 37, wherein R⁸⁹ is Cl or hydroxyl.
 39. The compound orsalt of claim 38, wherein R⁸⁹ is hydroxyl.
 40. The compound or salt ofclaim 1, wherein R⁶ is C₁₋₆ alkyl optionally substituted with hydroxyl.41. The compound or salt of claim 40, wherein R⁶ is selected from thegroup consisting of —CH(CH₃)OH, —CH(CH₃)₂, —C(CH₃)₃, —CH₂OH and —CH₂CH₃.42. The compound or salt of claim 41, wherein R⁶ is —CH(CH₃)OH.
 43. Thecompound or salt of claim 1, wherein R⁸ is —C₁₋₃ alkylene(C₆₋₁₀ aryl),wherein the C₆₋₁₀ aryl is optionally substituted with one or moresubstituents each independently selected from the group consisting ofhalogen, hydroxy, —NO₂, and C₁₋₆ alkoxy.
 44. The compound or salt ofclaim 43, wherein R⁸ is —C₁₋₂ alkylene(C₆ aryl), wherein the C₆ aryl isoptionally substituted with one or more substituents each independentlyselected from the group consisting of halogen, hydroxyl, —NO₂, and C₁₋₆alkoxy.
 45. The compound or salt of claim 44, wherein R⁸ is

wherein R¹⁵¹ is H, halogen, hydroxyl or C₁₋₃ alkoxy.
 46. The compound orsalt of claim 45, wherein R¹⁵¹ is Cl or hydroxyl.
 47. The compound orsalt of claim 46, wherein R¹⁵¹ is hydroxyl.
 48. The compound or salt ofclaim 1, wherein each of R⁹, R¹⁰, R¹¹, R¹², R¹³, R¹⁴, and R¹⁵ isindependently H or C₁₋₃ alkyl.
 49. The compound or salt of claim 48,wherein each of R⁹, R¹⁰, R¹¹, R¹³, R¹⁴, and R¹⁵ is H.
 50. The compoundor salt of claim 48, wherein R¹² is H or CH₃.
 51. The compound or saltof claim 50, wherein R¹² is H.
 52. The compound or salt of claim 1,wherein L is


53. The compound or salt of claim 1, wherein chiral centre *1 is in theS configuration, chiral centre *2 is in the S configuration, chiralcentre *3 is in the S configuration, chiral centre *4 is in the Rconfiguration, chiral centre *5 is in the S configuration, chiral centre*6 is in the S configuration, chiral centre *7 is in the Rconfiguration, and chiral centre *8 is in the R configuration.
 54. Apharmaceutical composition comprising a compound as defined in claim 1or a pharmaceutically acceptable salt thereof and a pharmaceuticallyacceptable carrier.
 55. A method of inhibiting an activity of an SSTR2receptor in a subject, the method comprising administering a compound ofclaim 1 or a pharmaceutically acceptable salt thereof, to a subject inneed thereof.
 56. A method of preventing or treating hypoglycemia in asubject, the method comprising administering a compound of claim 1, or apharmaceutically acceptable salt thereof, to a subject in need thereof.57. The method of 56, wherein the hypoglycemia is insulin-inducedhypoglycemia.
 58. A method of treating diabetes in a subject, the methodcomprising administering a compound of claim 1, or a pharmaceuticallyacceptable salt thereof, to a subject in need thereof.